Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

Roman Chrast; Gesine Saher; Klaus-Armin Nave; Mark H.G. Verheijen

doi:10.1194/jlr.r009761

Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

Chrast, Roman;Saher, Gesine;Nave, Klaus-Armin;Verheijen, Mark H.G. 2011-03-01 00:00:00 thematic review Thematic Review Series: Genetics of Human Lipid Diseases Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models 1, † † 1,§ Roman Chrast , * Gesine Saher , Klaus-Armin Nave , and Mark H. G. Verheijen Department of Medical Genetics,* University of Lausanne , Switzerland; Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine , Goettingen, Germany; and Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands Abstract The integrity of central and peripheral nervous and Schwann cells in the peripheral nervous system (PNS) system myelin is affected in numerous lipid metabolism dis- ( Fig. 1 ). The wrapping of myelin around an axonal seg- orders. This vulnerability was so far mostly attributed to the ment increases axonal resistance and enables clustering of extraordinarily high level of lipid synthesis that is required axonal ion channels at nodes of Ranvier ( 1 ). As such, my- for the formation of myelin, and to the relative autonomy in elinating glial cells shape the structural and electrical lipid synthesis of myelinating glial cells because of blood properties of axons resulting in a 10- to 100-fold increase barriers shielding the nervous system from circulating lip- in nerve conduction velocity ( 2, 3 ) and in a great reduc- ids. Recent insights from analysis of inherited lipid disor- tion of axonal energy consumption ( 4 ). ders, especially those with prevailing lipid depletion and from mouse models with glia-speciﬁ c disruption of lipid One of the prominent biochemical characteristics that metabolism, shed new light on this issue. The particular distinguishes myelin from other membranes is its high lipid composition of myelin, the transport of lipid-associated lipid-to-protein ratio; lipids account for at least 70% of the myelin proteins, and the necessity for timely assembly of the dry weight of myelin membranes ( Table 1 ) , which is also myelin sheath all contribute to the observed vulnerability the physical basis for its biochemical puriﬁ cation by su- of myelin to perturbed lipid metabolism. Furthermore, the crose gradient centrifugation ( 5 ). uptake of external lipids may also play a role in the forma- The myelin membrane contains myelin-speciﬁ c proteins tion of myelin membranes. In addition to an improved (e.g., myelin basic protein, myelin-associated glycopro- understanding of basic myelin biology, these data provide tein, and proteolipid protein), but no truly myelin-speciﬁ c a foundation for future therapeutic interventions aiming at preserving glial cell integrity in metabolic disorders. — lipids. Nevertheless, whereas all major lipid classes are Chrast, R., G. Saher, K-A. Nave, and M. H. G. Verheijen. present in myelin as in other membranes, myelin has its Lipid metabolism in myelinating glial cells: lessons from hu- characteristic lipid composition. The myelin membrane man inherited disorders and mouse models. J. Lipid Res . contains a high level of cholesterol of at least 26% by 2011. 52: 419–434. weight (or 52 mol%) ( Table 1 ) ( 6, 7 ). The importance of cholesterol for myelin production and maintenance has recently been reviewed ( 8 ). The myelin membrane is also MYELIN: A GIANT MEMBRANE ORGANELLE WITH substantially enriched in galactolipids (31% vs. 7% for SPECIFIC LIPID CHARACTERISTICS liver cell plasma membranes). Two glycosphingolipids, The rapid saltatory conduction of action potentials along axons is crucially dependent on myelination. The myelin membrane is an extended and highly specialized Abbreviations: ALD, adrenoleukodystrophy; ASPA, aspartoacylase; plasma membrane synthesized by myelinating glial cells: CD, Canavan disease; CGT, ceramide galactosyltransferase; CNS, cen- oligodendrocytes in the central nervous system (CNS), tral nervous system; CST, cerebroside sulfotransferase; CTX, Cerebro- tendinous xanthomatosis ; DHCR7, delta-7-reductase; FA2H, fatty acid 2-hydroxylase; HFA, hydroxyl fatty acid; NAA, N-acetylaspartic acid; OL, oligodendrocyte; PA, phosphatidic acid; PCD, pyruvate carboxyl- This work is supported by the European Union Grant EU-NEST 12702 (to ase deﬁ ciency; PLP, proteolipid protein; PNS, peripheral nervous sys- M.H.G.V.), Swiss National Science Foundation Grant PP00P3-124833/1 (to tem; RD, Refsum disease; SCAP, SREBP cleavage activating protein; R.C.), Deutsche Forschungsgemeinschaft (CMPB, to K-A.N.), and EU-FP7 SLOS, Smith-Lemli-Opitz syndrome; SREBP, sterol regulatory element- (NGIDD, Leukotreat, to K-A.N.). binding protein; SQS, squalene synthase; TD, Tangier disease; VLCFA, Manuscript received 9 July 2010 and in revised form 9 November 2010. very long-chain fatty acid. To whom correspondence should be addressed. Published, JLR Papers in Press, November 9, 2010 e-mail: [email protected]; [email protected] DOI 10.1194/jlr.R009761 Copyright © 2011 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr.org Journal of Lipid Research Volume 52, 2011 419 This is an Open Access article under the CC BY license. Fig. 1. Ultrastructural comparison of the mem- branes of a promyelinating versus a mature myelinat- ing glial cell. Electron micrographs of normal mouse sciatic nerves showing (A) promyelin ﬁ gure at postna- tal day 0 (P0) and (B) adult myelinated ﬁ ber (P100). The inner lip (also called inner mesaxon) of the my- elinating glial cell, which turns around the axon to form the membranous spiral of myelin, is depicted with an asterisk (*). Scale bar, 0.5 m. Sciatic nerve isolation and electron microscopy were done as de- scribed in ( 110 ). the monogalactosylsphingolipids cerebroside and sul- month) and is followed by myelination of the spinal cord fatide account for 14%–26% and 2%–7% of myelin lipids, and brain (CNS). The majority of myelin is assembled dur- respectively ( 9–11 ). When compared with hepatocyte and ing the ﬁ rst two years of postnatal life ( 14 ), but myelina- erythrocyte membranes, myelin membranes also contain a tion continues for 2–3 decades in the human cerebral higher proportion of saturated long-chain fatty acids ( Fig. white matter ( 15, 16 ). In rodents, myelination occurs pre- 2 ). Finally, the lipid content of myelin is also enriched in dominantly during the ﬁ rst month of life ( 17 ). The magni- plasmalogens (etherlipids). These glycerophospholipids, tude of the tasks that glial cells have to accomplish in a deﬁ ned by a vinyl ether double bond at the sn-1 position, short period of time is easily appreciated when visualizing account for 20% of the myelin phospholipid mass (com- the membrane expansion taking place during myelination pared with 18% in the average human phospholipid mass). ( Fig. 1 ). In rodents, it has been estimated that the myelin- Here, 70% of the total phosphatidylethanolamine in white membrane surface area of one glial cell expands at a rate 3 2 matter is plasmalogen, in contrast to only 5% in liver ( 12, of 5–50 × 10 m /day, compared with the surface area of 13 ). These lipid characteristics of myelin, together with the cell soma (i.e., the plasma membrane) of 0.3 × 10 the presence of myelin-speciﬁ c proteins, are likely re- m ( 18 ). This corresponds to an estimated 6,500-fold in- quired for myelin wrapping and/or to confer the speciﬁ c crease in membrane surface between an immature and a biophysical properties of myelin as an electrical “insula- fully myelinated oligodendrocyte ( 19 ). In rodents, the ex- tor”, as will be discussed below. pansion of the myelin membrane correlates with substan- During development of the human nervous system, my- tial accumulation of cholesterol and lipids in both the elination starts in the motor roots of the PNS (ﬁ fth fetal developing CNS and PNS ( 17, 20–22 ). More recently, tran- scriptional proﬁ ling of developing peripheral nerves shed light on the molecular cascades involved in PNS myelin assembly ( 23, 24 ). It was observed that transcripts encod- TABLE 1. Approximate lipid composition of the myelin membrane ing structural myelin proteins and enzymes involved in Liver Cell a b myelin lipid biosynthesis were expressed in a highly syn- Myelin Membrane Plasma Membrane chronized and timely fashion, suggesting a strict control of Lipid content (dry weight) 71% 34% a balanced and local production of these two key compo- Lipid class nents of myelin assembly. Relatively little is known about Cholesterol 26% 17% Phospholipids myelin lipid turnover in vivo, but studies in mice indicate PE 16% 7% a necessity to renew myelin lipids in adult life ( 25 ). PS 6% 4% PC 12% 24% PI 1% 4 SM 3% 20% MYELIN DEFECTS IN INHERITED DISEASES Glycolipids 31% 7% AFFECTING LIPID METABOLISM Other lipids 5% 17% From Norton and Poduslo 1973 ( 6 ): myelin of adult rat brain. The lipid-rich composition of myelin is likely to contrib- Comparable lipid amounts are present in myelin of rodent peripheral ute to the frequent occurrence of myelin defects in lipid nerve, with the exception of much higher SM levels (10–35%) ( 7 ). metabolism disorders, including hypomyelination (decreased From Dod and Gray, 1968 ( 164 ): plasma membrane of adult rat liver. The category ‘other lipids’ contains free fatty acids, triglycerides myelin production), dysmyelination (abnormally formed and cholesterol esters, which could be indicative for contamination by myelin), and demyelination (degenerative loss of myelin). other membranes. Comparable lipid amounts were found by Ray et al., Inherited forms of these diseases are particularly informa- 1968 ( 165 ). Bold numbers indicate percentages of lipids enriched in myelin, as discussed in the text. tive and provide direct insight into the underlying molecu- 420 Journal of Lipid Research Volume 52, 2011 Fig. 2. Fatty acid composition of myelin compared with other membranes. Depicted is the amount of fatty acid in mol percentage of total amount of fatty acids. Bold numbered and gray numbered lipids depict, re- spectively, strongly higher or lower levels of these fatty acids in myelin compared with hepatocytes or eryth- rocyte membranes. Myelin membrane of mouse sciatic nerve were isolated as described in ( 110, 163 ). Mouse erythrocyte membranes and hepatocyte phospholipids were isolated and analyzed according to ( 110, 163 ). It should be noted that under the isolation conditions used, amide bonds in sphingolipids are relatively stable. Hence, the very long-chain fatty acids found in myelin are not reﬂ ecting the high level of galactosphingolip- ids in myelin, but are more likely to result from a particular fatty acyl composition of the glycerophospho- lipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine). In addition, with the detection method used, the bar representing 18:1 fatty acids does not include 18:1 alcohol of plasmalogens, which nevertheless was previously detected to be very low in PNS myelin in mouse ( 110 ). lar mechanisms. These involve defects in metabolism of all CNS defects in white matter are common, often involving myelin enriched lipids: cholesterol, glycosphingolipid, corpus callosum absence or hypoplasia ( 36–42 ), and re- and long-chain fatty acids ( Table 2 ). In several of these ported to involve absence of myelin ( 42 ) and demyeli- disorders the defects are caused by lipotoxicity, a result of nation ( 43 ), but detailed analysis of myelin structure has the accumulation of various metabolic precursors involved not yet been described. The relative contribution of ei- in lipid biosynthesis to levels that are toxic to the myelin- ther cholesterol depletion or 7-dehydro-cholesterol and ating glial cells or at least interfere with normal myelin 8-dehydro-cholesterol accumulation in white matter ab- membrane structure [reviewed in ( 26–28 )]. Here, we will normalities is currently unclear. Interestingly, dietary cho- particularly discuss the disorders in which myelin defects lesterol supplementation has become the standard therapy are more likely caused by a primary defect in myelinating for SLOS and was reported to partially improve the neuro- glia that causes reduced levels of myelin-enriched lipids, logical status and white matter lipid abnormalities in some and are therefore more informative as to the contribution patients ( 36, 44–46 ). Remarkably, PNS myelin defects are of these lipids to the synthesis and function of myelin un- rarely reported for SLOS. The reason for this is currently der normal and pathological conditions (see section ‘Why unclear, but dietary lipid supplementation has also been are myelinating glial cells particularly vulnerable to lipid reported to improve a case of SLOS-associated demyelinat- metabolism disorders?’). ing polyneuropathy ( 47 ). Cholesterol disorders Mouse models of cholesterol disorders. Multiple mouse At least three different cholesterol-related disorders models of SLOS recapitulate morphological and biochem- cause defects in myelin ( Table 2 ). Of these, Cerebrotendi- ical aspects of the neuropathology of SLOS patients nous xanthomatosis (CTX) and Tangier disease (TD) lead ( 48–50 ). Although ventricular dilatation and partial agen- to accumulation of 7 -hydroxy-4-cholesten-3-one and cho- esis of corpus callosum was observed in one of these mod- lestanol (in CTX) and cholesterolesters (in TD), which els ( 50 ), the status of myelination was so far not analyzed are likely to underlie the myelin pathology [( 29–32 ), Fig. in DHCR7 mutant animals. The importance of local cho- 3 ] . Myelin defects due to reduced cholesterol levels are lesterol biosynthesis in myelinating glial cells was, however, possibly found in Smith-Lemli-Opitz syndrome (SLOS), addressed by conditional inactivation of squalene synthase which is caused by mutations in the gene encoding sterol (SQS; gene symbol fdft1 ) speciﬁ cally in oligodendrocytes ﬂ ox/ﬂ ox +/cre delta-7-reductase (DHCR7), the enzyme catalyzing the last and Schwann cells of fdft /cnp1 mice ( 51, 52 ) in step of cholesterol biosynthesis. This results in the eleva- which expression of cre recombinase (cre) was under con- tion of the cholesterol precursors 7-dehydro-cholesterol trol of the 2’:3 ′ -cyclic nucleotide 3 ′ -phosphodiesterase and 8-dehydro-cholesterol and in cholesterol deﬁ ciency in (cnp) promoter. In the CNS, SQS inactivation led to sub- all tissues ( 33–35 ). Patients with SLOS have multiple mal- stantial hypomyelination and reduced motor performance formations, cognitive impairment, and behavioral deﬁ cits. in 20-day-old SQS conditional mutants. The discrepancy Lipids in myelinating glial cells 421 422 Journal of Lipid Research Volume 52, 2011 TABLE 2. Inherited lipid disorders with myelin abnormalities Presumed Incidence or Myelin Defect Number of General Clinical Disease OMIM# Inheritance Patients Mutated Gene Function Features Onset CNS PNS Remarks Smith-Lemli-Opitz 270400 Autosomal 1-2:40,000 sterol delta-7-reductase cholesterol microcephaly mental mostly within the ﬁ rst ++ + - absence or syndrome recessive metabolism retardation hypotonia month of life hypoplasia of micrognathia polydactyly (early lethality corpus callosum ambiguous genitalia is common) detected cleft palate - reduced NCV in PNS (rare) Cerebrotendinous 213700 Autosomal 1:50,000 ( 166 ) sterol 27-hydroxylase cholesterol tendon xanthomas mental variable (6 to 60 years) ++ ++ - diffuse or focal xanthomatosis recessive metabolism retardation cerebellar cerebral and ataxia spasticity cataracts cerebellar white matter disease detected - reduced NCV in PNS Tangier disease 205400 Autosomal 100 patients ( 167 ) ATP-binding cassette cholesterol yellow-orange tonsils variable (2 to 67 years) +++ - PNS diagnostics: recessive transporter A1 transport splenomegaly neuromuscular hepatomegaly peripheral symptoms, neuropathy mostly normal NCV Dysmyelinating 612443 Autosomal 5 families ( 58 ) fatty acid 2-hydroxylase sphingolipid spasticity gait difﬁ culties 4 to 11 years + - hyperintensities leukodystrophy and recessive metabolism dystonia cognitive decline in parietal and spastic paraparesis occipital white with or without dystonia matter were detected Metachromatic 250100 Autosomal 0.6-2,5:100,000 arylsulfatase A sphingolipid ataxia variable (late infantile +++ +++ - hyperintensities leukodystrophy recessive ( 168, 169 ) metabolism muscle weakness to adult onset) detected in optic atrophy white matter mental deterioration - reduced NCV in white matter abnormalities PNS peripheral neuropathy Krabbe disease 245200 Autosomal 1:100,000 galactosylceramidase sphingolipid developmental regression variable, but 90% +++ +++ - diffuse cerebral recessive metabolism hyperirritability within ﬁ rst 6 months atrophy detected seizures of life (in this case - reduced NCV in optic atrophy the lethality before PNS the age of 2 years is common) Niemann-Pick disease 257200 Autosomal 0.5-1:100,000 (general sphingomyelin sphingolipid cherry-red maculae early onset (infancy) +++ + - reduced NCV in type A recessive population) phosphodiesterase-1 metabolism hepatomegaly xanthomas lethality before the PNS 3:100,000 (Ashkenazi muscle weakness age of 3 years Jews) ( 170 ) psychomotor retardation is common large vacuolated foam cells Sjogren-Larsson syndrome 270200 Autosomal 0.6:100,000 fatty aldehyde fatty acid spasticity mental retardation neurologic symptoms ++ - hyperintensities recessive in Sweden ( 171 ) dehydrogenase metabolism macular degeneration usually develop detected in short stature within 2 years white matter enamel hypoplasia after birth Peroxisome biogenesis 214100 Autosomal 1:100,000 peroxin 1 to 12 fatty acid facial dysmorphism lethality before the age +++ + - colpocephaly disorder recessive in USA ( 172 ) metabolism severe mental retardation of 1 year is common and mild plasmalogen hypotonia seizures impairment of synthesis hyporeﬂ exia/areﬂ exia myelination hepatomegaly detected Fig. 3. Human inherited and mouse experimental defects in the cholesterol biosynthesis pathway that cause myelin disorders. Solid line arrows depict a direct link between two steps, dashed line ar- rows imply intermediate steps that are not shown. Dark gray ovals show the positions of human disease genes; light gray oval shows the position of mutated genes in experimental mouse models. Sqs, squalene synthase; DHCR7, sterol delta-7-reductase; SLOS, Smith-Lemli-Opitz syndrome; CYP27A1, sterol 27-hydroxylase; CTX, Cerebrotendinous xanthomatosis; ABC1, ATP-binding cas- sette transporter A1; TD, Tangier disease. between the robust hypomyelination observed in SQS mouse mutants and the mild myelin defects observed in human SLOS is unclear, but may be related to the low amounts of cholesterol that are still produced in some forms of SLOS ( 33 ) and/or to the position of the defects leading to disruption of the cholesterol biosynthesis path- way, which is more upstream in SQS mouse mutants. Whereas the amount of myelin in SQS conditional mu- tants was decreased, its ultrastructure, lipid, and protein composition were not affected, suggesting a tight control mechanism matching the amount of myelin proteins pro- duced by glial cells to the available cholesterol. Interest- ingly, both hypomyelination and motor deﬁ cits improved over time. These observations suggest that cell autono- mous synthesis of cholesterol in oligodendrocytes is cru- cial for normal onset and progression of myelination. Cholesterol biosynthesis-deﬁ cient oligodendrocytes are, however, able to take up some cholesterol from their sur- rounding for limited myelin formation ( 51 ). The exact mechanism of this horizontal cholesterol transfer remains to be clariﬁ ed. In the PNS, the inactivation of cholesterol biosynthesis in Schwann cells also led to substantial hypo- myelination as detected by morphometric analysis of sciatic ﬂ ox/ﬂ ox +/cre nerves from fdft /cnp1 animals. Similar to oligo- dendrocytes, also Schwann cells are able to take up extra- cellular cholesterol because many axons in peripheral ﬂ ox/ﬂ ox +/cre nerves from fdft /cnp1 animals are ensheathed Lipids in myelinating glial cells 423 TABLE 2. Continued. Presumed Incidence or Myelin Defect Number of General Clinical Disease OMIM# Inheritance Patients Mutated Gene Function Features Onset CNS PNS Remarks Refsum disease 266500 Autosomal unknown phytanoyl-CoA fatty acid retinitis pigmentosa majority 20 to 30 years + ++ - white matter recessive hydroxylase metabolism peripheral neuropathy changes cerebellar ataxia deafness detected - reduced NCV in PNS Adrenoleukodystrophy 300100 X-linked 1:42,000 ( 173 ) ATP-binding cassette fatty acid adrenal insufﬁ ciency 7 to 20 years +++ + - white matter transporter D1 metabolism neurodegeneration changes blindness hearing loss detected spastic paraplegia paraparesis Canavan disease 271900 Autosomal generally rare aspartoacylase lipogenesis atonia of neck 2 to 4 months (death +++ - white matter recessive 1:13,000 in muscles hypotonia within ﬁ rst decade) changes Ashkenazi seizures blindness detected Jews ( 174 ) severe mental defect Pyruvate carboxylase 266150 Autosomal 1:250,000 ( 175 ) pyruvate carboxylase lipogenesis hepatomegaly mental Onset at birth or in early +++ - white matter deﬁ ciency recessive gene retardation psychomotor infancy changes retardation lactic acidemia detected Information provided is based on OMIM database (www.ncbi.nlm.nih.gov/omim/), additional references on presumed incidence, and references on myelin defects as provided in the text. by (albeit thin) myelin. These data have been corrobo- both galactosylceramides and sulfatides contain high pro- rated by in vitro experiments showing that extracellular portions (up to 50%) of 2-hydroxy fatty acids ( 59 ). Surpris- cholesterol increased myelination in both wild-type and ingly, the FA2H mutations result in demyelination of the mutant Schwann cells ( 52 ). Interestingly, detailed ultra- CNS, whereas PNS myelin abnormalities are not found, structural and biochemical analysis of mutant myelin re- suggesting there is a second fatty acid 2-hydroxylating ac- vealed substantial increase in the amount of noncompact tivity in human Schwann cells ( 57 ). myelin, probably as a consequence of defective myelin protein transport from the endoplasmic reticulum to the Mouse models of glycosphingolipid disorders. FA2H deﬁ - myelin sheath (see below). These data, together with a syn- cient mouse mutants lack 2-hydroxylated sphingolipids chronized downregulation of the mRNA expression for [hydroxyl fatty acid (HFA)-GalC and HFA-sulfatide] as multiple myelin proteins, suggest that in addition to its evaluated by thin-layer chromatography and MALDI-time- role as a major structural component of myelin, choles- of-ﬂ ight (TOF) MS ( 60 ). The absence of 2-hydroxylated terol plays a crucial role in coordinating myelin membrane sphingolipids in mice does not cause any detectable my- assembly. elin changes up to adulthood. However, myelin decom- paction was detected in aged (18 months) brain and was Glycosphingolipid disorders even more severe in peripheral nerve samples where signs Most of the myelin defects in glycosphingolipid disor- of myelin degeneration (e.g., decompaction and myelin ders are due to accumulation of glycosphingolipids or loss) were observed, clearly suggesting a role of HFAs in their precursors ( Table 2 ). Metachromatic leukodystro- long-term myelin stability. The presence of this discrete phy, Krabbe disease, and Niemann-Pick disease type A phenotype, or its late onset, suggests the possibility that lead to the accumulation of respectively sulfatides, galac- other models of glycosphingolipid disorders, including a tocerebrosides (and sphingosine), and sphingomyelin mouse model of Gaucher disease ( 61 ) or a knockout mouse [( 53–56 ) Fig. 4 ) . The accumulation of these lipids in my- for sphingomyelin synthase 2 ( 62 ), may have ultrastruc- elinating glial cells leads predominantly to cytotoxicity tural myelin changes that so far have not been detected. and demyelination. Myelin defects present in dysmyelinat- The role of the most abundant galactosphingolipids in ing leukodystrophy and spastic paraparesis with or without myelin was analyzed in mouse models disrupting either dystonia ( 57, 58 ), which is caused by a mutation in the sulfatide biosynthesis alone [cerebroside sulfotransferase gene encoding fatty acid 2-hydroxylase (FA2H), are, how- (CST) knockout mice] or disrupting both galactocerebro- ever, probably a consequence of reduced glycosphingo- side and sulfatide biosynthesis [UDP-galactose:ceramide lipid levels. The 2-hydroxylation of sphingolipid N -acyl galactosyltransferase (CGT) knockout mice, Fig. 4 ]. Char- chains catalyzed by the FA2H occurs during de novo cer- acterization of CST-deﬁ cient mice revealed that sulfatide amide synthesis. In accordance with the high level of FA2H plays a crucial role in maintenance of myelin structure and in mammalian central and peripheral nervous systems, organization of node and paranode ( 63, 64 ). Interestingly, whereas apparently normal myelin can be assembled in CST mutant animals, the myelin structure is disturbed with age, as reﬂ ected by uncompacted myelin sheaths in the CNS and nodal and paranodal abnormalities in both the CNS and PNS. The defective sulfatide biosynthesis also leads to axonal changes, as demonstrated by the loss of large axons in the CNS and the presence of axonal protru- sions in the PNS. In comparison, CGT mutant animals, which are unable to synthesize both galactocerebroside and sulfatide, have a similar but more marked myelin phe- notype because myelin abnormalities (including uncom- pacted areas and redundant myelin proﬁ les) are already present at P10 and evolve to substantial demyelination at / / P43 ( 65 ). Both CGT and CST animals develop a Fig. 4. Human inherited and mouse experimental defects in the glycosphingolipids synthesis pathway that cause myelin disorders. similar nodal phenotype characterized by disorganized para- Solid line arrows depict direct link between two steps, dashed line nodal loops and enlarged nodal gaps ( 63 ). Because the arrow implies intermediate steps that are not shown. Dark gray CGT animals accumulate HFA-Glc-Cer (which is nor- ovals show positions of human diseases; light gray ovals show the mally absent) in their myelin, it was suggested that HFA- position of mutated genes in experimental mouse models. ARSA, Glc-Cer could compensate partially for the absence of arylsulfatase A; ML, Metachromatic leukodystrophy; Cst, cerebro- galactolipids in these animals. However, inactivation of side sulfotransferase; GALC, galactosylceramidase; KD, Krabbe disease; Cgt, UDP-galactose:ceramide galactosyltransferase; Ugcg, UDP-glucose ceramide glucosyltransferase (Ugcg), which UDP-glucose ceramide glucosyltransferase; SMPD1, sphingomyelin prevented accumulation of HFA-Glc-Cer, did not lead to phosphodiesterase-1; NPD, Niemann-Pick disease type A; FA2H, any aggravation of myelin phenotype in double knockout fatty acid 2-hydroxylase; DLSP, Dysmyelinating leukodystrophy and ﬂ ox/ﬂ ox / Ugcg ; Cnp/Cre; CGT mice ( 66 ). These data there- spastic paraparesis with or without dystonia; Gal-Cer, galactocere- fore suggest that glial cells are able to assemble myelin in broside; Glc-Cer: glucocerebroside; 2-OH FA, 2-hydroxy fatty acids; the absence of glycolipids. FA, fatty acids. 424 Journal of Lipid Research Volume 52, 2011 Fig. 5. Human inherited and mouse experimental defects in fatty acids and plasmalogen metabolism that cause myelin disorders. Solid line arrows depict direct link between two steps, dashed line arrow im- plies intermediate steps that are not shown. Dashed line rectangles represent various lipid metabolic path- ways in the peroxisome. Dark gray ovals show posi- tions of human disease genes; light gray ovals show the position of mutated genes in experimental mouse models. Dhapat, dihydroxyacetone phosphate acyl- transferase; PHYH, phytanoyl-CoA hydroxylase; RD, Refsum disease; PEX1-12, peroxins; PBD, peroxisome biogenesis disorders; ALDH3A2, fatty aldehyde dehy- drogenase; SLS, Sjogren-Larsson syndrome; ABCD1, ATP-binding cassette transporter D1; ALD, adreno- leukodystrophy; VLCFA, very long-chain fatty acids. Fatty acid and plasmalogen disorders panied by progressive loss of CNS and PNS myelin levels from early adulthood on and dysmyelination predomi- S everal disorders in fatty acid metabolism are associated nantly in the PNS. It remains to be determined whether with defects in myelin that are mostly caused by the accu- myelinating glial cells are the primary cause, but these mulation of lipids ( Table 2 , Fig. 5 ). In Sjogren-Larsson data are indicative of the involvement of VLCFA in main- syndrome (SLS) mutations in fatty aldehyde dehydroge- tenance of the myelin membrane ( 75 ). nase result in the accumulation of long-chain fatty alco- Several mouse models have been generated for differ- hols ( 67 ), leading to CNS white matter abnormalities that ent peroxisomal disorders. Many of those recapitulate the are related to dysmyelination and hypomyelination ( 68, main pathological or biochemical defects observed in pa- 69 ). Lipid accumulation is also found in peroxisome tients, most often associated with lipotoxicity caused by disorders, such as Refsum disease [RD ( 70 )], adrenoleu- accumulation of metabolic intermediates, like VLCFA in kodystrophy [ALD ( 53 )], and peroxisome biogenesis RD and in ALD ( 76–81 ). It should be noted that satu- disorders ( 71 ). In RD, mutation of phytanoyl-CoA hydrox- rated VLCFAs, which are enriched in myelin ( Fig. 2 ), rely ylase leads to the accumulation of phytanic acid, a plant- fully on peroxisomes for -oxidation, which could under- derived fatty acid that is normally degraded by -oxidation lie the vulnerability of myelin for VLCFA accumulation in in peroxisomes. Accumulation of phytanic acid causes de- these disorders. Peroxisome biogenesis disorders have myelination, especially in the PNS. ALD is caused by muta- been modeled by inactivating different Pex genes (Pex2, tion of the ABCD1 protein which functions as a transporter Pex5, Pex13), which resulted in an early postnatal death of for the uptake of very long-chain fatty acids (VLCFAs) in affected animals, preventing myelin analysis ( 78–81 ). Mice peroxisomes. Because VLCFAs are metabolized in peroxi- carrying an oligodendrocyte speciﬁ c deletion of Pex 5 somes via -oxidation, myelinating glial cells in ALD- (CNPcre-Pex5 ( 82 )) assembled normal myelin, but sur- patients accumulate VLCFA, which causes dysmyelination prisingly within a few months, developed axonal defects but also inﬂ ammatory-induced demyelination. The latter followed by inﬂ ammatory demyelination. The observation may be caused by the failure to degrade arachidonic acid- that the PEX5-deﬁ cient oligodendrocytes are not able to derived eicosanoids ( 72, 73 ). Peroxisome biogenesis disor- maintain axonal integrity, even in the absence of obvious ders of Zellweger syndrome occur when any one of 12 demyelination, indicates a role of oligodendrocyte peroxi- peroxins involved in the import of peroxisomal proteins is some-associated lipid metabolism in axonal support. In mutated [for a recent review, see ( 74 )]. The consequent addition, the remarkable inﬂ ammatory demyelination ob- partial or complete peroxisome dysfunction results in de- served in CNPcre-Pex5 mice suggest a role for abnormal fective - and -oxidation, subsequent accumulation of lipid metabolism in inﬂ ammation ( 82 ), as also observed in fatty acids, leading to myelin defects as also seen in ALD or human ALD disease ( 72, 83, 84 ). Interestingly, polyunsat- RD. In addition, myelin defects due to reduced lipid levels urated VLCFAs, such as arachidonic acid, are substrates are found in Zellweger syndrome as well, because the per- for the synthesis of eicosanoids, which are lipid inﬂ amma- oxisomal anabolic lipid pathway involved in ether lipid tory mediators ( 85, 86 ). Peroxisomes play a major role in synthesis is disrupted ( Fig. 5 ), resulting in plasmalogen de- the degradation of eicosanoids ( 72, 87, 88 ). The fact that ﬁ ciency and consequent mild hypomyelination and dys- the VLCFAs in myelin are saturated and not unsaturated myelination, especially in the CNS. might reduce the risk of generating too high levels of lipid Mouse models of fatty acid disorders. As shown in Fig. 2 , inﬂ ammatory mediators. Together, these data suggest that myelin is speciﬁ cally enriched in saturated VLCFAs (C22:0- peroxisomes in myelinating glial cells are likely to be im- portant for protection against lipid induced inﬂ ammation, C24:0). Mice carrying a deletion of ceramide synthase 2, by degrading VLCFA and eicosanoids. The observations an enzyme that is mostly involved in synthesis of ceramides with VLCFAs, show myelin with ceramide species that no on CNP-cre-PEX5 mice furthermore indicate that peroxi- longer have VLCFAs ( C22) but instead are enriched in some-associated lipid metabolism is not required in oligo- dendrocytes for myelin membrane synthesis per se. However, short-chain fatty acids ( 75 ). These changes where accom- Lipids in myelinating glial cells 425 mice in which Pex5 is lacking in all neural cells [Nestin-cre PEX5 mice ( 80 )] do show dysmyelination, indicating that, in CNP-cre-PEX5 mice, oligodendrocytes may take up per- oxisome-derived lipids from other neural cells and utilize these lipids for myelin membrane synthesis. Mouse models of plasmalogen disorders. The Pex2, Pex5, or Pex13 knockout mouse models of peroxisome biogene- sis disorder have reduced nervous system plasmalogen lev- els ( 78–81 ), but how this contributes to myelin lipid defects is difﬁ cult to establish due to the contribution of the other defects in peroxisome lipid metabolism ( Fig. 5 ). The Pex7 ( 77 ) and dihydroxyacetone phosphate acyl transferase ( 89 ) knockout mice were generated as mouse models of rhizomeluic chondrodysplasia type 1 and 2, respectively, both peroxisomal disorders that are characterized by a shortage of ether lipids and delays in myelination ( 80 ). In Pex7 knockout mice, a small reduction in CNS myelin pro- tein levels was observed, and PNS nerves showed thinning of the myelin sheath and a reduced motor nerve conduc- tion velocity ( 76 ). In the knockout mouse for Dhapat, a peroxisomal enzyme essential for plasmalogen synthesis, reduced CNS myelination was observed together with ab- normal paranodal structure and reduced corpus callosum Fig. 6. Human inherited and mouse experimental defects in conduction velocity ( 90 ). Together, these studies suggest a general lipid metabolism that cause myelin disorders. Solid line structural role of plasmalogens in myelin membrane, al- arrows depict direct link between two steps, dashed line arrows im- though ultrastructural studies remain necessary to unravel plies intermediate steps that are not shown. Dashed line circle rep- resents the citric acid cycle in mitochondria. Dark gray oval shows the precise role of plasmalogens in myelination. Further- positions of human disease genes; light gray oval shows the position more, plasmalogens are described to function as a sink of of mutated genes in an experimental mouse model. PC, pyruvate car- polyunsaturated fatty acids (PUFAs) ( 91 ) and as such pro- boxylase; PCD, pyruvate carboxylase deﬁ ciency; ASPA, asparto- posed to have a protective role against the effects of acetylase; CD, Canavan disease; NAA, N-acetylaspartic acid; FA, PUFA accumulation as seen in peroxisome disorders fatty acids. ( 92 ). Indeed, Pex7:Abcd1 knockout mice show an in- crease in VLCFA accumulation and inﬂ ammatory demy- Mouse models of general lipid disorders. Two mouse mod- elination ( 76 ). els of CD, in which ASPA is deleted, show myelin vacuoliza- tion similar to human Canavan patients ( 102, 103 ), and General lipogenesis disorders reduced brain levels for acetate, myelin lipids, and myelin Several myelin disorders are caused by defects in early proteins ( 104, 105 ). Labeling studies have shown that NAA steps in the synthesis of lipids ( Table 2 , Fig. 6 ). Pyruvate is a major source of acetate for lipid synthesis during brain carboxylase deﬁ ciency [PCD ( 93, 94 )] is caused by a muta- development and that neuronal-derived NAA supplies ace- tion in pyruvate carboxylase, an enzyme required for the tyl groups for myelin lipid synthesis ( 106, 107 ). Its quanti- synthesis of oxaloacetate of pyruvate in the tricarboxylic tative signiﬁ cance for myelin synthesis is not completely acid cycle, which is found in glial cells, predominantly as- clear because in most cell types, the enzyme ATP-citrate lyase trocytes ( 95–97 ). Several biochemical pathways rely on the provides the acetyl groups for fatty acid synthesis. Madha- tricarboxylic acid cycle, such as biosynthesis of fatty acids, varao and colleagues ( 104 ) recently suggested that the nonessential amino acids, and gluconeogenesis. Conse- lowering of acetate in ASPA knockout mice is sufﬁ cient to quently, PCD patients show CNS hypomyelination, whereas decrease myelin synthesis. However, ultrastructural analy- PNS myelin defects have not been described. Canavan dis- sis of myelin during development remains to be done in ease [CD ( 98 )] is caused by a mutation in aspartoacylase order to determine the precise consequence of ASPA deﬁ - (ASPA), an enzyme that in the rodent nervous system was ciency on myelin formation. Recently, it was shown that shown to be predominantly expressed in oligodendrocytes defective survival and differentiation of immature oligo- ( 99 ) and is involved in the deacetylation of the nervous dendrocytes may also be implicated in CD ( 108 ). Further- system speciﬁ c metabolite N-acetylaspartic acid (NAA), more, the toxic effects of NAA in myelin vacuolization should thus generating free acetate in the brain. Patients affected not be neglected ( 109 ). by CD show accumulation of neuronal NAA and reduced The role of glial lipid synthesis in myelination was re- levels of acetate in oligodendrocytes, the latter is generally cently studied by Verheijen et al. ( 110 ). It was shown that thought to limit fatty acid and membrane lipid synthesis the acute phase of myelin lipid synthesis is regulated by and to underlie the spongiform myelin degeneration, sterol regulatory element-binding protein (SREBP) cleav- while leaving neurons intact ( 100, 101 ). age activating protein (SCAP), an activator of SREBPs. 426 Journal of Lipid Research Volume 52, 2011 P0cre-SCAP mice, which carry a Schwann cell speciﬁ c de- Glycosphingolipids consist of a ceramide backbone, letion of SCAP, showed congenital hypomyelination, and formed by a long-chain fatty acyl residue linked by its am- had a loss of SREBP-mediated gene expression involved in ide bond to a long-chain sphingosine base that binds the cholesterol and fatty acids synthesis. Interestingly, SCAP functional group galactosyl or sulfatide. They pack tightly mutant Schwann cells were able to slowly synthesize mye- and have the remarkable property that their ﬂ uid/solid phase transition temperature is above body temperature, lin in an external lipid-dependent fashion, resulting in my- so that glycolipids have a solid ‘gel’ phase at body temper- elin membrane defects that were associated with abnormal ature ( 118–120 ). Accordingly, CGT knockout mice, which lipid composition. Saturated VLCFAs (C22:0 and C24:0) lack glycosphingolipids, have increased myelin membrane were found to be reduced in myelin membranes, while poly-unsaturated fatty acids (C18:2, C22:6, C24:2, C25:2 ﬂ uidity and therefore increased ion permeability, which may disrupt saltatory conduction ( 121 ). In addition to and C26:2) were increased. The reduced saturation level this, the anionic glycol group may provide an electronic of long-chain fatty acids resulted in an increase in disorder shielding on the outside of the myelin membrane and of acyl groups in the myelin lipid bilayer, which may lead thereby contribute to the electric isolation by the myelin to altered packaging of proteins in the membrane ( 111 ) membrane and thus nerve conduction velocity. Interest- and consequent ultrastructural myelin abnormalities. ingly, glycosphingolipids are solubilized by cholesterol These observations also showed that glial cells are able to ( 122 ), and both lipids are predominantly present in the take up lipids from the extracellular environment and uti- outer leaﬂ et of the myelin membrane. Asymmetric distri- lize these for myelin membrane synthesis, which is in line bution of lipids between two bilayer leaﬂ ets contributes to with the observation of Saher et al. ( 51, 52 ) on CNPcre- curving of membranes ( 122 ). This suggests a role of gly- SQS mice in which cholesterol deﬁ cient myelinating glial cosphingolipids and cholesterol in regulating ﬂ uidity and cells are able to slowly synthesize myelin. curving of myelin membranes, which could be particularly relevant for the paranodal loops structure. In line with this WHY ARE MYELINATING GLIAL CELLS is the nodal phenotype of galactolipids-lacking CGT and PARTICULARLY VULNERABLE TO LIPID CST knockout mice ( 63 ). METABOLISM DISORDERS? Plasmalogens are a sub-class of ether phospholipids, which are glycerol-derived compounds that carry an ether- The unique lipid composition of myelin critically linked carbohydrate chain on the ﬁ rst carbon of glycerol contributes to its function as opposed to ester-linked fatty acid chain in classical phos- Much of the vulnerability of myelin for lipid defects is pholipid containing a vinyl group next to the ether bond. caused by the fact that myelin membrane assembly re- The particular role of plasmalogens in membranes has not quires an extraordinary amount of lipids, especially for the been elucidated, but they are thought to play a role in lipids that are enriched in myelin: galactolipids, choles- membrane fusion processes and membrane dynamics. terol, plasmalogens, and fatty acids. As described above, They increase membrane ﬂ uidity by lowering the transi- for each of these lipid classes, human myelin disorders tion of phospholipid mixtures from a lamellar to a liquid have been described in which the pathophysiology is re- crystalline phase and stimulate the formation of nonbi- lated to lipotoxicity as a result of the accumulation of met- layer lipid structures when present in high concentration abolic precursors for myelin lipids. The vulnerability of ( 123 ). Accordingly, plasmalogens could be involved in my- myelin for lipid disorders could, however, also relate to elin membrane formation or maintenance by potentiating biochemical properties of each lipid class for functioning membrane dynamics ( 124 ). of the myelin membrane. The brain is enriched in long PUFAs like DHA (c22:6) Cholesterol is one of the most important regulators of ( 125 ). However, this enrichment is not manifested in lipid organization in the membrane. The hydroxyl group myelin, which instead contains high levels of saturated of cholesterol interacts with the polar head group of other VLCFA, and has a particularly high C18:1/C18:2 ratio (see lipids, whereas the rigid body of cholesterol is situated Fig. 2 ). Because of its high degree of saturation, phospho- along side the fatty acid tails of lipids in the membrane lipids containing these fatty acids may decrease membrane and can help to order these tails. The increased lateral ﬂ uidity and give a higher degree of fatty acid ordering in ordering of lipids that is caused by cholesterol conse- the membrane, which prevents intercalation of polar mol- quently affects the biophysical properties of the membrane ecules into the lipids. Together with the extra-long length by decreasing ﬂ uidity and reducing the permeability of of the acyl chains, this will provide a thick permeability polar molecules, like ions, for example ( 112–115 ). By con- barrier for ions and as such contribute to electric insula- trast, too much ordering is detrimental because this could tion of the axon. slow down the diffusion of membrane proteins and decrease Considering their structural role in the membrane, we the bending capacity of the membrane ( 112, 114, 116, 117 ). view that many of the lipids that are enriched in myelin Furthermore, some membrane proteins bind tightly to play a role in its axon-insulating property: the electric cholesterol as discussed below. Together, this gives choles- shielding in the outer leaﬂ et by glycolipids, the thick and terol the capacity to regulate membrane ﬂ uidity and to stabi- ordered bilayer made by the long and saturated FA, and lize and seal the membrane, all functions that seem critical the further sealing of the outer leaﬂ et by cholesterol. It for the insulating function of the myelin membrane ( 8 ). should be noted that the speciﬁ c myelin lipid composition Lipids in myelinating glial cells 427 is also likely to be related to proper packing of the myelin ing glial cells are synthesizing most of the lipids themselves, membrane. Changes in lipid composition affect lipid- but 2 ) myelinating glial cells are still able to synthesize my- protein interactions causing an altered packing of proteins elin when endogenous lipid synthesis has been shut down, in the membrane ( 111 ). For instance, proteins and lipids albeit at a very low level. This indicates that these cells have may work synergistically to provide proper structure to my- the capacity to take up lipids from the extracellular envi- elin membranes ( 126 ). In line with this, interference with ronment. Accordingly, transcription analysis in rodents endogenous Schwann cell lipid metabolism in P0cre-SCAP showed that lipoprotein receptors are expressed by oligo- mutant mice increases the unsaturation level of fatty acids dendrocytes ( 127 ) and that expression of the low density in myelin and is accompanied by ultrastructural defects in lipoprotein receptor (LDLR) gene in the PNS is elevated myelin membrane packing ( 110 ). with myelination ( 24 ) although the LDLR gene was found Together, these data suggest that lipids may control in- not to be required for PNS remyelination ( 128 ). Which li- sulation of the axon and proper structure of the myelin poprotein receptors are involved in the uptake of lipids membrane ( Fig. 7 ). Both of these aspects are clearly af- and exactly where on the glial cell they can be found to fected in many lipid metabolic disorders, but it remains to support membrane growth ( Fig. 1 ) is currently unclear. be determined whether small functional defects on nerve The exact contribution of extracellular lipid supply for mye- function in certain cases are caused by more subtle changes lin membrane synthesis under normal conditions remains in myelin lipid composition that affect axonal insulation. to be determined, but is likely to be small ( Fig. 7 ). Defects It is furthermore tempting to speculate that myelinating in glial lipid synthesis will therefore consequently lead to glial cells may control nerve conduction velocity by regula- defective myelin membrane synthesis. tion of its myelin lipid content. Myelin lipids regulate the transport and localization of Timely myelination requires extraordinarily high levels of myelin proteins lipid synthesis together with uptake of extracellular lipids In addition to the above mentioned synchronized ex- Much of the vulnerability of myelin for lipid defects is pression of transcripts encoding structural myelin proteins caused by the fact that myelin membrane assembly re- and enzymes involved in myelin lipid biosynthesis, recent quires an extraordinary amount of lipids. The observations data suggest that glial lipid levels regulate myelin protein on CNPcre-SQS ko mice ( 51, 52 ) and P0cre-SCAP ko mice trafﬁ cking and thus also myelin assembly ( 52 )( 129 ). In oli- ( 110 ) have led to two important conclusions: 1 ) myelinat- godendrocytes, proteolipid protein (PLP) associates with lipid rafts before exiting the Golgi apparatus, suggesting that myelin lipid and proteins assemble in the Golgi com- plex. Indeed, the cholesterol- and galactosylceramide-rich lipid rafts were shown to be required for proper sorting of PLP to myelin ( 129 ). In line with this, certain mutations in PLP perturb interactions with cholesterol and lipid rafts, which may contribute to dysmyelination as found in spastic paraplegia ( 130 ). Similarly, disrupted Schwann cell cho- lesterol biosynthesis led to partial mislocalization of my- elin protein P0, resulting in noncompaction of the myelin membrane and hypomyelination ( 52 ). Additional cell cul- ture experiments demonstrated that this defect could be restored by cholesterol supplementation, and showed the critical role of the myelin protein P0 cholesterol recogni- tion/interaction amino acid consensus motif for its cor- rect trafﬁ cking from endoplasmic reticulum to the myelin compartment. Furthermore, elevation of extracellular cho- lesterol or lipoprotein levels was demonstrated to increase Fig. 7. Schematic diagram of the various roles of lipids in myeli- myelination by Schwann cells in vitro ( 52, 110 ). Together, nating glial cells. Gray ovals show the processes that are affected by these data suggest that lipids may control myelin protein lipid metabolism and involved in myelinated ﬁ ber function. High lipid levels, which are required for synthesis of a full myelin mem- trafﬁ cking and thereby assembly and compaction of the my- brane, are ensured by both the endogenous synthesis of lipids as by elin membrane ( Fig. 7 ). This lipid-mediated control mech- the uptake of lipids from the extracellular environment. Lipids inﬂ u- anism of myelin protein sorting is likely to be deregulated ence myelinating glial cell differentiation and trafﬁ cking of myelin in lipid metabolic disorders, but whether and how it is used proteins to the myelin membrane. The unique lipid composition by myelinating glial cells to control myelin membrane syn- of the myelin membrane is required for proper myelin membrane thesis under healthy conditions remains to be determined. wrapping (compaction) and electrostatic isolation of the axon from extracellular environment, thereby promoting saltatory conduc- tion and conduction velocity. Question marks show processes with Lipids regulate differentiation of myelinating glial cells a potential effect on myelin ﬁ ber function: the inﬂ uence of lipid- The regulatory role of lipids in differentiation of myeli- speciﬁ c diets on myelin lipid dependent processes, and the possi- nating glial cells was demonstrated in oligodendrocytes ble role of myelin lipids in metabolic support of the axon. See text and in Schwann cells. Both the cell culture experiments for further explanation. 428 Journal of Lipid Research Volume 52, 2011 and the data from CGT and CST knockout animals re- somal biogenesis factor 5 (Pex5) led to generation of animals vealed an increased number of terminally differentiated with disrupted peroxisomal function in oligodendrocytes oligodendrocytes (OLs) in the absence of galactosphingo- and Schwann cells [see above ( 82 )]. Interestingly, al- lipids ( 131, 132 ). Based on these results, two putative reg- though the affected animals were able to assemble normal ulatory mechanisms involving galactosphingolipids were myelin, they developed progressive axonal loss followed by suggested: either they could play a direct role in cell adhe- demyelination. Based on these data it was suggested that sion necessary for correct timing of OL differentiation or the observed axonal loss could be, at least partially, a con- they can have an indirect role affecting signaling proteins sequence of disrupted glial -oxidation normally executed present in plasma membrane thus disturbing OL differen- in peroxisomes, leading to a diminished capacity to meta- tiation ( 132 ). In the PNS, phosphatidic acid (PA) was shown bolically support the underlying axons ( 73 ). A similar hy- to affect Schwann cell differentiation ( 133 ). Demyelina- pothesis suggesting the role of lipids in “energy-on-demand” tion in Lpin1 mutant mice was suggested to be mediated supply for active axons was proposed based on expression by increased levels of PA. Subsequent cell culture experi- analysis of genes encoding proteins involved in lipid me- ments demonstrated that PA induces Schwann cell dedif- tabolism in the adult peripheral nerve ( 24, 136 ). Although ferentiation via activation of the MEK-Erk pathway revealing further clariﬁ cation of the involvement of lipids in axonal its role in glial cell fate determination ( 133 ) ( Fig. 7 ). support is still needed, it was shown that the expression of sterol response binding protein 1c (Srebp1c), which is the key transcriptional regulator of storage lipid metabolism, MYELIN LIPIDS AS DETERMINANTS FOR is affected in Schwann cells of a rodent model of diabetic NERVE FIBER FUNCTION peripheral neuropathy ( 137 ). Together, therefore, these data suggest that local glial lipid metabolism plays a crucial The process of myelination represents an interesting para- role not only in myelination but also in glial support of digm to study the metabolism and transport of lipids. Myeli- underlying axons. nation by rodent glial cells is, both in vivo and in vitro, ﬁ nalized within a one- to two-week interval. Because during Implications for therapeutic interventions that target this period a myelinating glial cell needs to expand its mem- lipid metabolism brane up to 6,500 times, one can consider these cells as “lipid A working strategy against lipotoxicity would be to use producing factories”. For instance, transcriptional analysis of drugs that inhibit lipid accumulation. For instance, phar- myelinating glial cells clearly revealed that the most coregu- lated group of genes expressed during the period of myelina- macological targeting of the cholesterol pathway, by statin- induced inhibition of HMG-CoA reductase, is used in CTX tion are lipid biosynthesis-related transcripts ( 23, 24 ). to inhibit the accumulation of cholestan ( 138 ). Impor- Lipids as markers for myelin membrane integrity tantly, statins are widely used for the treatment of hyper- and function cholesterolemia, and some statins, e.g., Lovastatin and Simvastatin, are able to cross the blood-brain barrier ( 139 ). Much of the structure and function of myelin is depen- Remarkably, statins can ameliorate remyelination in an dent on its lipid content. Lipids may therefore be used as markers for myelin membrane integrity and associated animal model of multiple sclerosis (MS) ( 140–143 ), possi- nerve ﬁ ber function. The C18:1/C18:2 ratio is a well- bly via augmenting survival and differentiation of oligo- dendrocyte progenitors, and therefore have been tested in described marker for the progression of myelination of the MS trials ( 144, 145 ). However, statins induce the forma- PNS ( 7 ) and the CNS ( 134 ). In addition, a high level of PUFA in PNS myelin suggests a strong contribution of ex- tion of abnormal myelin-like membrane sheets in primary ogenous lipids in building of the myelin membrane ( 110 ). oligodendrocytes in vitro, due to impairment of cholesterol- dependent myelin protein transport ( 146 ), which indi- High cholesterol levels are required for the formation of cates a risk of the use of statins for myelin membrane compact myelin (with high P0), with low cholesterol levels resulting in increased amounts of noncompact myelin integrity. In addition, statins are reported to increase the [with myelin-associated glycoprotein (MAG)] ( 52 ). This risk of developing peripheral neuropathy ( 147 ), although there is some controversy concerning the exact amplitude suggests that the cholesterol content of myelin is indica- of this risk, which furthermore appeared to be reversible tive for its compaction status. Dedifferentiation of myeli- nating Schwann cells in the Lpin1 mutant appeared to be and will need further study ( 148, 149 ). The major contri- mediated by high PA levels ( 133 ). This suggests that high bution of endogenous lipid metabolism by myelinating glial cells implies that inhibition of glial lipid metabolism, PA levels are indicative for an active anti-myelination pro- especially during the active period of myelination, may un- gram, although it remains to be determined whether PA is also instrumental in regulating (de)differentiation in derlie the development of demyelinating neuropathy, and other paradigms, e.g., during development or injury. as such warrants for care in the use of lipid-lowering drugs especially during late pregnancies and early postnatal Myelin lipids provide direct support to axonal function; development. a hypothesis Extracellular supply of lipids may be a working strategy A possible role of myelinating glial cells in trophic sup- for treatment of lipid deﬁ cit in myelinating glial cells. Ob- servations of mice with lipid-deﬁ cient glial cells show that port of underlying axons was recently suggested ( 135 ). Previous data demonstrated that inactivation of peroxi- myelinating glial cells are able to take up lipids from the Lipids in myelinating glial cells 429 extracellular environment ( 51, 52, 150 ). This is, however, of local hypolipidemia induced by pathological conditions complicated by the blood-nerve barrier and the blood- like genetic lipid disorders, myelinating glial cells may be brain barrier that shield, respectively, the PNS and CNS able to obtain lipids derived from the circulation or from from lipids in the circulation ( 151, 152 ). Therefore, the other nervous system compartments, albeit at a very low nervous system is classically viewed as being largely autono- level. mous in lipid metabolism. Despite this dogma, dietary ap- As summarized in this review, our knowledge about the proaches to rescue lipid deﬁ cits are used in several lipid role of lipids in myelin biology increased substantially disorders to treat myelin defects. In SLOS, cholesterol from the analysis of inherited myelin disorders with defec- supplementation leads to good biochemical and physical tive lipid metabolism and their related mouse models. These new data point to a far more complex role of lipids changes in nonneuronal tissues ( 153 ). Changes in neu- ronal tissues are limited, also because of the inability to in myelinating glial cells than solely being building blocks reverse developmental defects, although striking behav- for the myelin membrane ( Fig. 7 ). Lipid metabolism is im- ioral improvements involving both CNS and PNS function- portant for glial cell development and function; lipids af- fect glial cell differentiation, are involved in myelin protein ing were found ( 44, 45, 154 ). In a rodent model for CD, glyceryltriacetate supplementation was recently reported trafﬁ cking and myelin compaction, and may potentially to improve motor performance and myelin lipid content contribute to mature myelinating glial cell support of en- ( 155 ). In Zellweger patients, alkyl-glycerol supplementa- wrapped axons. Importantly, these new data also show that despite the requirement of timely local glial lipid synthesis tion to rescue plasmalogen deﬁ ciency has been performed for normal myelination, myelinating glial cells are able to with only little success ( 156 ), which may be related to the other peroxisomal defects that are not related to plasmalo- take up lipids from the surrounding environment. To- gen deﬁ ciency in these patients. Interestingly, in Pex7 gether, these insights may contribute to the development of therapeutic approaches aiming at the preservation of knockout mice, a model for rhizomeluic chondrodysplasia myelin under pathological conditions that affect lipid me- type 1, alkyl-glycerol supplementation improves PNS plas- malogen levels and nerve function (P. Brites, personal tabolism. communication). The above-described changes may not involve lipid up- The authors thank Dr. J. F. Brouwers for advice and fatty acid take by the nervous system, but instead be indirect conse- analysis. quences of lipid supplementation. For instance, lipid metabolism in Schwann cells is under the inﬂ uence of the nutritional status of mice through a mechanism probably REFERENCES involving insulin signaling ( 137 ). Recent studies have also shed light on novel mechanisms of cholesterol exchange 1 . Barres , B. A. 2008 . The mystery and magic of glia: a perspective on between the CNS and circulating lipoproteins under cer- their roles in health and disease. Neuron . 60 : 430 – 440 . 2 . Franz , D. N. , and A. Iggo . 1968 . Conduction failure in myelinated tain physiological or pathological conditions. Saito et al. and non-myelinated axons at low temperatures. J. Physiol. 199 : ( 157 ) recently showed that deletion of SQS in neural 319 – 345 . stem cells led to neuronal cell death, however, not of pro- 3 . Waxman , S. G. 1980 . Determinants of conduction velocity in mye- linated nerve ﬁ bers. Muscle Nerve . 3 : 141 – 150 . genitor cells at the subventricular zone that protected 4 . Hartline , D. K. , and D. R. Colman . 2007 . Rapid conduction and themselves against cholesterol deprivation by promoting the evolution of giant axons and myelinated ﬁ bers. Curr. Biol. 17 : angiogenesis and consequently raising their lipoprotein R29 – R35 . 5 . Norton , W. T. , and S. E. Poduslo . 1973 . Myelination in rat brain: cholesterol supply from the circulation. Furthermore, it method of myelin isolation. J. Neurochem. 21 : 749 – 757 . was reported that speciﬁ c loss of brain ABCA1, which is 6 . Norton , W. T. , and S. E. Poduslo . 1973 . Myelination in rat brain: required for efﬂ ux of cellular cholesterol, not only pro- changes in myelin composition during brain maturation. J. Neurochem. 21 : 759 – 773 . duced the expected reduction in brain cholesterol, but 7 . Garbay , B. , A. M. Heape , F. Sargueil , and C. Cassagne . 2000 . remarkably, also led to an apparently compensatory in- Myelin synthesis in the peripheral nervous system. Prog. Neurobiol. crease in the speciﬁ c uptake of esteriﬁ ed cholesterol from 61 : 267 – 304 . plasma HDL particles into the CNS ( 158 ). The observed 8 . Saher , G. , and M. Simons . 2010 . Cholesterol and myelin biogene- sis. Subcell. Biochem. 51 : 489 – 508 . increase in HDL receptor SR-B1 in brain capillaries of 9 . Norton , W. T. , and W. Cammer . 1984 . Isolation and characteriza- these mice, together with the recent ﬁ nding that lipopro- tion of myelin. In Myelin. P. Morell, editor. Plenum, New York. tein receptors in brain capillary cells can be used for tar- 147–180. 10 . Stoffel , W. , and A. Bosio . 1997 . Myelin glycolipids and their func- geting of compounds across the blood-brain barrier ( 159 ), tions. Curr. Opin. Neurobiol. 7 : 654 – 661 . indicate that the shielding of the CNS from circulating lip- 11 . Eckhardt , M. 2008 . The role and metabolism of sulfatide in the ids may not be as strict as thought for a long time. This is nervous system. Mol. Neurobiol. 37 : 93 – 103 . 12 . Nagan , N. , and R. A. Zoeller . 2001 . Plasmalogens: biosynthesis certainly the case for circulating unsaturated fatty acids. and functions. Prog. Lipid Res. 40 : 199 – 229 . For instance, PNS myelin in P0cre-SCAP mutant mice con- 13 . Balakrishnan , S. , H. Goodwin , and J. N. Cumings . 1961 . The dis- tains more polyunsaturated fatty acids, and have higher tribution of phosphorus-containing lipid compounds in the hu- man brain. J. Neurochem. 8 : 276 – 284 . C18:2 levels, which is consistent with an increased uptake 14 . Morell , P. , and R.H. Quarles. 1999 . Myelin formation, structure of essential fatty acids from external sources ( 160 ). Consis- and biochemistry. In Basic Neurochemistry. J. S. George, B. W. tent with this, circulating fatty acids are incorporated into Agranoff, R. W. Albers, S. F. Fisher, and M. D. Uhler, editors. Lippincott-Raven, Philedelphia. adult myelin ( 161, 162 ). Taken together, in the situation 430 Journal of Lipid Research Volume 52, 2011 15 . Sowell , E. R. , B. S. Peterson , P. M. Thompson , S. E. Welcome , A. MRS ﬁ ndings in Smith-Lemli-Opitz syndrome. Neuroradiology . 46 : L. Henkenius , and A. W. Toga . 2003 . Mapping cortical change 3 – 14 . across the human life span. Nat. Neurosci. 6 : 309 – 315 . 37 . Kelley , R. I. , and R. C. Hennekam . 2000 . The Smith-Lemli-Opitz 16 . Yakovlev , P. I. , and A. R. Lecours . 1967 . The myelogenetic cycles syndrome. J. Med. Genet. 37 : 321 – 335 . of regional maturation of the brain. In Regional Development of 38 . Curry , C. J. , J. C. Carey , J. S. Holland , D. Chopra , R. Fineman , the Brain in Early Life. A. Minkowski, editor. Blackwell Scientiﬁ c, M. Golabi , S. Sherman , R. A. Pagon , J. Allanson , S. Shulman , et al . Oxford. 3–70. 1987 . Smith-Lemli-Opitz syndrome-type II: multiple congenital 17 . Muse , E. D. , H. Jurevics , A. D. Toews , G. K. Matsushima , and P. anomalies with male pseudohermaphroditism and frequent early Morell . 2001 . Parameters related to lipid metabolism as markers lethality. Am. J. Med. Genet. 26 : 45 – 57 . of myelination in mouse brain. J. Neurochem. 76 : 77 – 86 . 39 . Ryan , A. K. , K. Bartlett , P. Clayton , S. Eaton , L. Mills , D. Donnai , 18 . Baron , W. , and D. Hoekstra . 2009 . On the biogenesis of myelin R. M. Winter , and J. Burn . 1998 . Smith-Lemli-Opitz syndrome: membranes: sorting, trafﬁ cking and cell polarity. FEBS Lett. 584 : a variable clinical and biochemical phenotype. J. Med. Genet. 35 : 1760 – 1770 . 558 – 565 . 19 . Webster , H. D. 1971 . The geometry of peripheral myelin sheaths 40 . Berry , R. , H. Wilson , J. Robinson , C. Sandlin , W. Tyson , J. during their formation and growth in rat sciatic nerves. J. Cell Biol. Campbell , R. Porreco , and D. Manchester . 1989 . Apparent Smith- 48 : 348 – 367 . Lemli-Opitz syndrome and Miller-Dieker syndrome in a family 20 . Heape , A. , H. Juguelin , M. Fabre , F. Boiron , B. Garbay , M. with segregating translocation t(7;17)(q34;p13.1). Am. J. Med. Fournier , J. Bonnet , and C. Cassagne . 1986 . Correlation between Genet. 34 : 358 – 365 . the morphology and the lipid and protein compositions in the 41 . Cherstvoy , E. D. , G. I. Lazjuk , T. I. Ostrovskaya , I. A. Shved , G. I. peripheral nervous system of individual 8-day-old normal and Kravtzova , I. W. Lurie , and A. I. Gerasimovich . 1984 . The Smith- trembler mice. Brain Res. 390 : 173 – 180 . Lemli-Opitz syndrome. A detailed pathological study as a clue to a 21 . Heape , A. , H. Juguelin , M. Fabre , F. Boiron , and C. Cassagne . etiological heterogeneity. Virchows Arch. 404 : 413 – 425 . 1986 . A quantitative developmental study of the peripheral nerve 42 . Ness , G. C. , D. Lopez , O. Borrego , and E. Gilbert-Barness . 1997 . lipid composition during myelinogenesis in normal and trembler Increased expression of low-density lipoprotein receptors in a mice. Brain Res. 390 : 181 – 189 . Smith-Lemli-Opitz infant with elevated bilirubin levels. Am. J. 22 . Heape , A. , F. Boiron , and C. Cassagne . 1987 . A developmental Med. Genet. 68 : 294 – 299 . study of fatty acyl group contents in the peripheral nervous system 43 . Fierro , M. , A. J. Martinez , J. W. Harbison , and S. H. Hay . 1977 . of normal and trembler mice. Neurochem. Pathol. 7 : 157 – 167 . Smith-Lemli-Opitz syndrome: neuropathological and ophthalmo- 23 . Nagarajan , R. , N. Le , H. Mahoney , T. Araki , and J. Milbrandt . logical observations. Dev. Med. Child Neurol. 19 : 57 – 62 . 2002 . Deciphering peripheral nerve myelination by using 44 . Elias , E. R. , M. B. Irons , A. D. Hurley , G. S. Tint , and G. Salen . Schwann cell expression proﬁ ling. Proc. Natl. Acad. Sci. USA . 1997 . Clinical effects of cholesterol supplementation in six pa- 99 : 8998 – 9003 . tients with the Smith-Lemli-Opitz syndrome (SLOS). Am. J. Med. 24 . Verheijen , M. H. , R. Chrast , P. Burrola , and G. Lemke . 2003 . Local Genet. 68 : 305 – 310 . regulation of fat metabolism in peripheral nerves. Genes Dev. 17 : 45 . Irons , M. , E. R. Elias , D. Abuelo , M. J. Bull , C. L. Greene , V. P. 2450 – 2464 . Johnson , L. Keppen , C. Schanen , G. S. Tint , and G. Salen . 1997 . 25 . Ando , S. , Y. Tanaka , Y. Toyoda , and K. Kon . 2003 . Turnover of Treatment of Smith-Lemli-Opitz syndrome: results of a multicen- myelin lipids in aging brain. Neurochem. Res. 28 : 5 – 13 . ter trial. Am. J. Med. Genet. 68 : 311 – 314 . 26 . Dyck , P. J. , and P. K. Thomas . 2005 . Lysosomal and peroxi- 46 . Porter , F. D. 2000 . RSH/Smith-Lemli-Opitz syndrome: a multi- somal disorders. In Peripheral Neuropathy. Elsevier Saunders, ple congenital anomaly/mental retardation syndrome due to an Philadelphia, PA. 1845–1882. inborn error of cholesterol biosynthesis. Mol. Genet. Metab. 71 : 27 . Wanders , R. J. , S. Ferdinandusse , P. Brites , and S. Kemp . 2010 . 163 – 174 . Peroxisomes, lipid metabolism and lipotoxicity. Biochim. Biophys. 47 . Starck , L. , I. Bjorkhem , E. M. Ritzen , B. Y. Nilsson , and U. von Acta . 1801 : 272 – 280 . Dobeln . 1999 . Beneﬁ cial effects of dietary supplementation in a 28 . Horster , F. , R. Surtees , and G. F. Hoffmann . 2005 . Disorders of disorder with defective synthesis of cholesterol. A case report of intermediary metabolism: toxic leukoencephalopathies. J. Inherit. a girl with Smith-Lemli-Opitz syndrome, polyneuropathy and pre- Metab. Dis. 28 : 345 – 356 . cocious puberty. Acta Paediatr. 88 : 729 – 733 . 29 . Verrips , A. , L. H. Hoefsloot , G. C. Steenbergen , J. P. Theelen , 48 . Fitzky , B. U. , F. F. Moebius , H. Asaoka , H. Waage-Baudet , L. R. A. Wevers , F. J. Gabreels , B. G. van Engelen , and L. P. van Xu , G. Xu , N. Maeda , K. Kluckman , S. Hiller , H. Yu , et al . 2001 . den Heuvel . 2000 . Clinical and molecular genetic characteristics 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reduc- of patients with cerebrotendinous xanthomatosis. Brain . 123 : tase suppresses sterol biosynthesis in a mouse model of Smith- 908 – 919 . Lemli-Opitz/RSH syndrome. J. Clin. Invest. 108 : 905 – 915 . 30 . Gallus , G. N. , M. T. Dotti , and A. Federico . 2006 . Clinical and 49 . Wassif , C. A. , P. Zhu , L. Kratz , P. A. Krakowiak , K. P. Battaile , F. F. molecular diagnosis of cerebrotendinous xanthomatosis with Weight , A. Grinberg , R. D. Steiner , N. A. Nwokoro , R. I. Kelley , a review of the mutations in the CYP27A1 gene. Neurol. Sci. 27 : et al . 2001 . Biochemical, phenotypic and neurophysiological 143 – 149 . characterization of a genetic mouse model of RSH/Smith–Lemli– 31 . Pietrini , V. , N. Rizzuto , C. Vergani , F. Zen , and F. Ferro Milone . Opitz syndrome. Hum. Mol. Genet. 10 : 555 – 564 . 1985 . Neuropathy in Tangier disease: A clinicopathologic study 50 . Correa-Cerro , L. S. , C. A. Wassif , L. Kratz , G. F. Miller , J. P. and a review of the literature. Acta Neurol. Scand. 72 : 495 – 505 . Munasinghe , A. Grinberg , S. J. Fliesler , and F. D. Porter . 2006 . 32 . Pollock , M. , H. Nukada , R. W. Frith , J. P. Simcock , and S. Allpress . Development and characterization of a hypomorphic Smith- 1983 . Peripheral neuropathy in Tangier disease. Brain . 106 : Lemli-Opitz syndrome mouse model and efﬁ cacy of simvastatin 911 – 928 . therapy. Hum. Mol. Genet. 15 : 839 – 851 . 33 . Neklason , D. W. , K. M. Andrews , R. I. Kelley , and J. E. Metherall . 51 . Saher , G. , B. Brugger , C. Lappe-Siefke , W. Mobius , R. Tozawa , 1999 . Biochemical variants of Smith-Lemli-Opitz syndrome. Am. J. M. C. Wehr , F. Wieland , S. Ishibashi , and K. A. Nave . 2005 . High Med. Genet. 85 : 517 – 523 . cholesterol level is essential for myelin membrane growth. Nat. 34 . Witsch-Baumgartner , M. , B. U. Fitzky , M. Ogorelkova , H. G. Kraft , Neurosci. 8 : 468 – 475 . F. F. Moebius , H. Glossmann , U. Seedorf , G. Gillessen-Kaesbach , 52 . Saher , G. , S. Quintes , W. Mobius , M. C. Wehr , E. M. Kramer- G. F. Hoffmann , P. Clayton , et al . 2000 . Mutational spectrum in Albers , B. Brugger , and K. A. Nave . 2009 . Cholesterol regulates the Delta7-sterol reductase gene and genotype-phenotype cor- the endoplasmic reticulum exit of the major membrane protein relation in 84 patients with Smith-Lemli-Opitz syndrome. Am. J. P0 required for peripheral myelin compaction. J. Neurosci. 29 : Hum. Genet. 66 : 402 – 412 . 6094 – 6104 . 35 . Ciara , E. , M. J. Nowaczyk , M. Witsch-Baumgartner , E. Malunowicz , 53 . von Figura , K. , V. Gieselmann , and J. Jaeken . 2001 . Metachromatic E. Popowska , A. Jezela-Stanek , M. Piotrowicz , J. S. Waye , G. leukodystrophy. In The Metabolic And Molecular Basis of Utermann , and M. Krajewska-Walasek . 2004 . DHCR7 mutations Inherited Disease. C. R. Scriver, A. L. Beaudet, D. Valle, W. S. Sly, and genotype-phenotype correlation in 37 Polish patients with editors. McGraw Hill, New York. 3695–3724. Smith-Lemli-Opitz syndrome. Clin. Genet. 66 : 517 – 524 . 54 . Landrieu , P. , and G. Said . 1984 . Peripheral neuropathy in type A 36 . Caruso , P. A. , T. Y. Poussaint , A. A. Tzika , D. Zurakowski , L. G. Niemann-Pick disease. A morphological study. Acta Neuropathol. Astrakas , E. R. Elias , C. Bay , and M. B. Irons . 2004 . MRI and 1H 63 : 66 – 71 . Lipids in myelinating glial cells 431 55 . Suzuki , K. 2003 . Globoid cell leukodystrophy (Krabbe’s disease): 74 . Van Veldhoven , P. P. 2010 . Biochemistry and genetics of inher- update. J. Child Neurol. 18 : 595 – 603 . ited disorders of peroxisomal fatty acid metabolism. J. Lipid Res. 56 . Schuchman , E. H. , and R. J. Desnick . 2001 . Niemann-Pick dis- 51 : 2863 – 2895 . ease types A and B: acid sphingomyelinase deﬁ ciencies. In The 75 . Imgrund , S. , D. Hartmann , H. Farwanah , M. Eckhardt , R. Metabolic and Molecular Basis of Inherited Disease. C. R. Scriver, Sandhoff , J. Degen , V. Gieselmann , K. Sandhoff , and K. Willecke . A. L. Beaudet, W. S. Sly, D. Valle, B. Childs, K. W. Kinzler, and B. 2009 . Adult ceramide synthase 2 (CERS2)-deﬁ cient mice exhibit Vogelstein, editors. McGraw-Hill, New York. 3589–3610. myelin sheath defects, cerebellar degeneration, and hepatocarci- 57 . Edvardson , S. , H. Hama , A. Shaag , J. M. Gomori , I. Berger , D. nomas. J. Biol. Chem. 284 : 33549 – 33560 . Soffer , S. H. Korman , I. Taustein , A. Saada , and O. Elpeleg . 2008 . 76 . Brites , P. , P. A. Mooyer , L. El Mrabet , H. R. Waterham , and R. J. Mutations in the fatty acid 2-hydroxylase gene are associated with Wanders . 2009 . Plasmalogens participate in very-long-chain fatty leukodystrophy with spastic paraparesis and dystonia. Am. J. Hum. acid-induced pathology. Brain . 132 : 482 – 492 . Genet. 83 : 643 – 648 . 77 . Brites , P. , A. M. Motley , P. Gressens , P. A. Mooyer , I. Ploegaert , 58 . Dick , K. J. , M. Eckhardt , C. Paisan-Ruiz , A. A. Alshehhi , C. V. Everts , P. Evrard , P. Carmeliet , M. Dewerchin , L. Schoonjans , Proukakis , N. A. Sibtain , H. Maier , R. Shariﬁ , M. A. Patton , W. et al . 2003 . Impaired neuronal migration and endochondral os- Bashir , et al . 2010 . Mutation of FA2H underlies a complicated siﬁ cation in Pex7 knockout mice: a model for rhizomelic chon- form of hereditary spastic paraplegia (SPG35). Hum. Mutat. 31 : drodysplasia punctata. Hum. Mol. Genet. 12 : 2255 – 2267 . E1251 – E1260 . 78 . Maxwell , M. , J. Bjorkman , T. Nguyen , P. Sharp , J. Finnie , C. 59 . Alderson , N. L. , B. M. Rembiesa , M. D. Walla , A. Bielawska , J. Paterson , I. Tonks , B. C. Paton , G. F. Kay , and D. I. Crane . 2003 . Bielawski , and H. Hama . 2004 . The human FA2H gene encodes a Pex13 inactivation in the mouse disrupts peroxisome biogenesis fatty acid 2-hydroxylase. J. Biol. Chem. 279 : 48562 – 48568 . and leads to a Zellweger syndrome phenotype. Mol. Cell. Biol. 23 : 60 . Zoller , I. , M. Meixner , D. Hartmann , H. Bussow , R. Meyer , V. 5947 – 5957 . Gieselmann , and M. Eckhardt . 2008 . Absence of 2-hydroxylated 79 . Faust , P. L. , and M. E. Hatten . 1997 . Targeted deletion of the sphingolipids is compatible with normal neural development PEX2 peroxisome assembly gene in mice provides a model for but causes late-onset axon and myelin sheath degeneration. J. Zellweger syndrome, a human neuronal migration disorder. J. Cell Neurosci. 28 : 9741 – 9754 . Biol. 139 : 1293 – 1305 . 61 . Enquist , I. B. , C. Lo Bianco , A. Ooka , E. Nilsson , J. E. Mansson , M. 80 . Baes , M. , and P. Aubourg . 2009 . Peroxisomes, myelination, and Ehinger , J. Richter , R. O. Brady , D. Kirik , and S. Karlsson . 2007 . axonal integrity in the CNS. Neuroscientist . 15 : 367 – 379 . Murine models of acute neuronopathic Gaucher disease. Proc. 81 . Baes , M. , P. Gressens , E. Baumgart , P. Carmeliet , M. Casteels , Natl. Acad. Sci. USA . 104 : 17483 – 17488 . M. Fransen , P. Evrard , D. Fahimi , P. E. Declercq , D. Collen , 62 . Hailemariam , T. K. , C. Huan , J. Liu , Z. Li , C. Roman , M. et al . 1997 . A mouse model for Zellweger syndrome. Nat. Genet. Kalbfeisch , H. H. Bui , D. A. Peake , M. S. Kuo , G. Cao , et al . 2008 . 17 : 49 – 57 . Sphingomyelin synthase 2 deﬁ ciency attenuates NFkappaB activa- 82 . Kassmann , C. M. , C. Lappe-Siefke , M. Baes , B. Brugger , tion. Arterioscler. Thromb. Vasc. Biol. 28 : 1519 – 1526 . A. Mildner , H. B. Werner , O. Natt , T. Michaelis , M. Prinz , 63 . Marcus , J. , S. Honigbaum , S. Shroff , K. Honke , J. Rosenbluth , and J. Frahm , et al . 2007 . Axonal loss and neuroinﬂ ammation J. L. Dupree . 2006 . Sulfatide is essential for the maintenance of caused by peroxisome-deﬁ cient oligodendrocytes. Nat. Genet. CNS myelin and axon structure. Glia . 53 : 372 – 381 . 39 : 969 – 976 . 64 . Hoshi , T. , A. Suzuki , S. Hayashi , K. Tohyama , A. Hayashi , Y. 83 . Powers , J. M. , Y. Liu , A. B. Moser , and H. W. Moser . 1992 . The Yamaguchi , K. Takeuchi , and H. Baba . 2007 . Nodal protrusions, inﬂ ammatory myelinopathy of adreno-leukodystrophy: cells, ef- increased Schmidt-Lanterman incisures, and paranodal disorga- fector molecules, and pathogenetic implications. J. Neuropathol. nization are characteristic features of sulfatide-deﬁ cient periph- Exp. Neurol. 51 : 630 – 643 . eral nerves. Glia . 55 : 584 – 594 . 84 . Ito , M. , B. M. Blumberg , D. J. Mock , A. D. Goodman , A. B. Moser , 65 . Coetzee , T. , N. Fujita , J. Dupree , R. Shi , A. Blight , K. Suzuki , and H. W. Moser , K. D. Smith , and J. M. Powers . 2001 . Potential B. Popko . 1996 . Myelination in the absence of galactocerebroside environmental and host participants in the early white matter and sulfatide: normal structure with abnormal function and re- lesion of adreno-leukodystrophy: morphologic evidence for gional instability. Cell . 86 : 209 – 219 . CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1- 66 . Saadat , L. , J. L. Dupree , J. Kilkus , X. Han , M. Traka , R. L. Proia , mediated lipid antigen presentation. J. Neuropathol. Exp. Neurol. G. Dawson , and B. Popko . 2010 . Absence of oligodendroglial 60 : 1004 – 1019 . glucosylceramide synthesis does not result in CNS myelin abnor- 85 . elMasry , M. N. , and R. R. Rich . 1989 . Prostaglandin E2 selectively malities or alter the dysmyelinating phenotype of CGT-deﬁ cient increases interferon gamma receptor expression on human CD8+ mice. Glia . 58 : 391 – 398 . lymphocytes. J. Clin. Invest. 83 : 1436 – 1440 . 67 . Rizzo , W. B. , G. Carney , and Z. Lin . 1999 . The molecular basis 86 . Jozefowski , S. , R. Biedron , M. Bobek , and J. Marcinkiewicz . 2005 . of Sjogren-Larsson syndrome: mutation analysis of the fatty alde- Leukotrienes modulate cytokine release from dendritic cells. hyde dehydrogenase gene. Am. J. Hum. Genet. 65 : 1547 – 1560 . Immunology . 116 : 418 – 428 . 68 . Willemsen , M. A. , M. Van Der Graaf , M. S. Van Der Knaap , A. 87 . Schepers , L. , M. Casteels , J. Vamecq , G. Parmentier , P. P. Van Heerschap , P. H. Van Domburg , F. J. Gabreels , and J. J. Rotteveel . Veldhoven , and G. P. Mannaerts . 1988 . Beta-oxidation of the car- 2004 . MR imaging and proton MR spectroscopic studies in boxyl side chain of prostaglandin E2 in rat liver peroxisomes and Sjogren-Larsson syndrome: characterization of the leukoenceph- mitochondria. J. Biol. Chem. 263 : 2724 – 2731 . alopathy. AJNR Am. J. Neuroradiol. 25 : 649 – 657 . 88 . Ferdinandusse , S. , T. Meissner , R. J. Wanders , and E. Mayatepek . 69 . van Domburg , P. H. , M. A. Willemsen , J. J. Rotteveel , J. G. de Jong , 2002 . Identiﬁ cation of the peroxisomal beta-oxidation enzymes H. O. Thijssen , A. Heerschap , J. R. Cruysberg , R. J. Wanders , F. involved in the degradation of leukotrienes. Biochem. Biophys. Res. J. Gabreels , and P. M. Steijlen . 1999 . Sjogren-Larsson syndrome: Commun. 293 : 269 – 273 . clinical and MRI/MRS ﬁ ndings in FALDH-deﬁ cient patients. 89 . Rodemer , C. , T. P. Thai , B. Brugger , T. Kaercher , H. Werner , K. Neurology . 52 : 1345 – 1352 . A. Nave , F. Wieland , K. Gorgas , and W. W. Just . 2003 . Inactivation 70 . Wierzbicki , A. S. , M. D. Lloyd , C. J. Schoﬁ eld , M. D. Feher , of ether lipid biosynthesis causes male infertility, defects in eye de- and F. B. Gibberd . 2002 . Refsum’s disease: a peroxisomal dis- velopment and optic nerve hypoplasia in mice. Hum. Mol. Genet. order affecting phytanic acid alpha-oxidation. J. Neurochem. 80 : 12 : 1881 – 1895 . 727 – 735 . 90 . Teigler , A. , D. Komljenovic , A. Draguhn , K. Gorgas , and W. W. 71 . Steinberg , S. J. , G. Dodt , G. V. Raymond , N. E. Braverman , A. B. Just . 2009 . Defects in myelination, paranode organization and Moser , and H. W. Moser . 2006 . Peroxisome biogenesis disorders. Purkinje cell innervation in the ether lipid-deﬁ cient mouse cere- Biochim. Biophys. Acta . 1763 : 1733 – 1748 . bellum. Hum. Mol. Genet. 18 : 1897 – 1908 . 72 . Mayatepek , E. , M. Baumann , T. Meissner , F. Hanefeld , and G. C. 91 . Tamby , J. P. , P. Reinaud , and G. Charpigny . 1996 . Preferential es- Korenke . 2003 . Role of leukotrienes as indicators of the inﬂ am- teriﬁ cation of arachidonic acid into ethanolamine phospholipids matory demyelinating reaction in x–linked cerebral adrenoleu- in epithelial cells from ovine endometrium. J. Reprod. Fertil. 107 : kodystrophy. J. Neurol. 250 : 1259 – 1260 . 23 – 30 . 73 . Kassmann , C. M. , and K. A. Nave . 2008 . Oligodendroglial impact 92 . Brites , P. , H. R. Waterham , and R. J. Wanders . 2004 . Functions on axonal function and survival - a hypothesis. Curr. Opin. Neurol. and biosynthesis of plasmalogens in health and disease. Biochim. 21 : 235 – 241 . Biophys. Acta . 1636 : 219 – 231 . 432 Journal of Lipid Research Volume 52, 2011 93 . Marin-Valencia , I. , C. R. Roe , and J. M. Pascual . 2010 . Pyruvate 113 . Sankaram , M. B. , and T. E. Thompson . 1990 . Modulation of phos- carboxylase deﬁ ciency: mechanisms, mimics and anaplerosis. Mol. pholipid acyl chain order by cholesterol. A solid-state 2H nuclear Genet. Metab. 101 : 9 – 17 . magnetic resonance study. Biochemistry . 29 : 10676 – 10684 . 94 . Schiff , M. , V. Levrat , C. Acquaviva , C. Vianey-Saban , M. O. 114 . Huang , J. , and G. W. Feigenson . 1999 . A microscopic interaction Rolland , and N. Guffon . 2006 . A case of pyruvate carboxylase de- model of maximum solubility of cholesterol in lipid bilayers. ﬁ ciency with atypical clinical and neuroradiological presentation. Biophys. J. 76 : 2142 – 2157 . Mol. Genet. Metab. 87 : 175 – 177 . 115 . Kakorin , S. , U. Brinkmann , and E. Neumann . 2005 . Cholesterol 95 . Cesar , M. , and B. Hamprecht . 1995 . Immunocytochemical exam- reduces membrane electroporation and electric deformation of ination of neural rat and mouse primary cultures using monoclo- small bilayer vesicles. Biophys. Chem. 117 : 155 – 171 . nal antibodies raised against pyruvate carboxylase. J. Neurochem. 116 . Pan , J. , S. Tristram-Nagle , and J. F. Nagle . 2009 . Effect of cho- 64 : 2312 – 2318 . lesterol on structural and mechanical properties of membranes 96 . Shank , R. P. , G. S. Bennett , S. O. Freytag , and G. L. Campbell . depends on lipid chain saturation. Phys. Rev. E Stat. Nonlin. Soft 1985 . Pyruvate carboxylase: an astrocyte-speciﬁ c enzyme impli- Matter Phys. 80 : 021931 . cated in the replenishment of amino acid neurotransmitter pools. 117 . Hofsass , C. , E. Lindahl , and O. Edholm . 2003 . Molecular dynamics Brain Res. 329 : 364 – 367 . simulations of phospholipid bilayers with cholesterol. Biophys. J. 97 . Murin , R. , M. Cesar , B. S. Kowtharapu , S. Verleysdonk , and B. 84 : 2192 – 2206 . Hamprecht . 2009 . Expression of pyruvate carboxylase in cultured 118 . Wang , T. Y. , and J. R. Silvius . 2003 . Sphingolipid partitioning into oligodendroglial, microglial and ependymal cells. Neurochem. Res. ordered domains in cholesterol-free and cholesterol-containing 34 : 480 – 489 . lipid bilayers. Biophys. J. 84 : 367 – 378 . 98 . Namboodiri , A. M. , A. Peethambaran , R. Mathew , P. A. Sambhu , 119 . Kulkarni , K. , D. S. Snyder , and T. J. McIntosh . 1999 . Adhesion J. Hershﬁ eld , J. R. Moffett , and C. N. Madhavarao . 2006 . Canavan between cerebroside bilayers. Biochemistry . 38 : 15264 – 15271 . disease and the role of N-acetylaspartate in myelin synthesis. Mol. 120 . Ruocco , M. J. , D. Atkinson , D. M. Small , R. P. Skarjune , E. Oldﬁ eld , Cell. Endocrinol. 252 : 216 – 223 . and G. G. Shipley . 1981 . X-ray diffraction and calorimetric study 99 . Madhavarao , C. N. , J. R. Moffett , R. A. Moore , R. E. Viola , M. A. of anhydrous and hydrated N-palmitoylgalactosylsphingosine (ce- Namboodiri , and D. M. Jacobowitz . 2004 . Immunohistochemical rebroside). Biochemistry . 20 : 5957 – 5966 . localization of aspartoacylase in the rat central nervous system. 121 . Bosio , A. , E. Binczek , W. F. Haupt , and W. Stoffel . 1998 . Composi- J. Comp. Neurol. 472 : 318 – 329 . tion and biophysical properties of myelin lipid deﬁ ne the neuro- 100 . Adachi , M. , L. Schneck , J. Cara , and B. W. Volk . 1973 . Spongy logical defects in galactocerebroside- and sulfatide-deﬁ cient mice. degeneration of the central nervous system (van Bogaert and J. Neurochem. 70 : 308 – 315 . Bertrand type; Canavan’s disease). A review. Hum. Pathol. 4 : 122 . van Meer , G. , D. R. Voelker , and G. W. Feigenson . 2008 . Membrane 331 – 347 . lipids: where they are and how they behave. Nat. Rev. Mol. Cell Biol. 101 . Gascon , G. G. , P. T. Ozand , A. Mahdi , A. Jamil , A. Haider , J. 9 : 112 – 124 . Brismar , and M. al-Nasser . 1990 . Infantile CNS spongy degener- 123 . Glaser , P. E. , and R. W. Gross . 1994 . Plasmenylethanolamine facil- ation–14 cases: clinical update. Neurology . 40 : 1876 – 1882 . itates rapid membrane fusion: a stopped-ﬂ ow kinetic investigation 102 . Matalon , R. M. , and K. Michals-Matalon . 2000 . Spongy degener- correlating the propensity of a major plasma membrane constit- ation of the brain, Canavan disease: biochemical and molecular uent to adopt an HII phase with its ability to promote membrane ﬁ ndings. Front. Biosci. 5 : D307 – D311 . fusion. Biochemistry . 33 : 5805 – 5812 . 103 . Traka , M. , R. L. Wollmann , S. R. Cerda , J. Dugas , B. A. Barres , 124 . Glaser , P. E. , and R. W. Gross . 1995 . Rapid plasmenylethano l- and B. Popko . 2008 . Nur7 is a nonsense mutation in the mouse amine-selective fusion of membrane bilayers catalyzed by an aspartoacylase gene that causes spongy degeneration of the CNS. isoform of glyceraldehyde-3-phosphate dehydrogenase: discrimi- J. Neurosci. 28 : 11537 – 11549 . nation between glycolytic and fusogenic roles of individual iso- 104 . Madhavarao , C. N. , P. Arun , J. R. Moffett , S. Szucs , S. Surendran , forms. Biochemistry . 34 : 12193 – 12203 . R. Matalon , J. Garbern , D. Hristova , A. Johnson , W. Jiang , et al . 125 . Sastry , P. S. 1985 . Lipids of nervous tissue: composition and me- 2005 . Defective N-acetylaspartate catabolism reduces brain ace- tabolism. Prog. Lipid Res. 24 : 69 – 176 . tate levels and myelin lipid synthesis in Canavan’s disease. Proc. 126 . Hu , Y. , I. Doudevski , D. Wood , M. Moscarello , C. Husted , C. Natl. Acad. Sci. USA . 102 : 5221 – 5226 . Genain , J. A. Zasadzinski , and J. Israelachvili . 2004 . Synergistic in- 105 . Ledeen , R. W. , J. Wang , G. Wu , Z. H. Lu , G. Chakraborty , M. teractions of lipids and myelin basic protein. Proc. Natl. Acad. Sci. Meyenhofer , S. K. Tyring , and R. Matalon . 2006 . Physiological USA . 101 : 13466 – 13471 . role of N-acetylaspartate: contribution to myelinogenesis. Adv. 127 . Zhao , S. , X. Hu , J. Park , Y. Zhu , Q. Zhu , H. Li , C. Luo , R. Han , Exp. Med. Biol. 576 : 131–143; discussion 361–133. N. Cooper , and M. Qiu . 2007 . Selective expression of LDLR and 106 . Namboodiri , A. M. , J. R. Moffett , P. Arun , R. Mathew , S. VLDLR in myelinating oligodendrocytes. Dev. Dyn. 236 : 2708 – 2712 . Namboodiri , A. Potti , J. Hershﬁ eld , B. Kirmani , D. M. Jacobowitz , 128 . Goodrum , J. F. , K. A. Fowler , J. D. Hostettler , and A. D. Toews . and C. N. Madhavarao . 2006 . Defective myelin lipid synthesis as a 2000 . Peripheral nerve regeneration and cholesterol reutiliza- pathogenic mechanism of Canavan disease. Adv. Exp. Med. Biol. tion are normal in the low-density lipoprotein receptor knockout 576 : 145–163; discussion 361–143. mouse. J. Neurosci. Res. 59 : 581 – 586 . 107 . Chakraborty , G. , P. Mekala , D. Yahya , G. Wu , and R. W. Ledeen . 129 . Simons , M. , E. M. Kramer , C. Thiele , W. Stoffel , and J. Trotter . 2001 . Intraneuronal N-acetylaspartate supplies acetyl groups for 2000 . Assembly of myelin by association of proteolipid protein myelin lipid synthesis: evidence for myelin-associated aspartoacy- with cholesterol- and galactosylceramide-rich membrane do- lase. J. Neurochem. 78 : 736 – 745 . mains. J. Cell Biol. 151 : 143 – 154 . 108 . Kumar , S. , J. C. Biancotti , R. Matalon , and J. de Vellis . 2009 . Lack 130 . Kramer-Albers , E. M. , K. Gehrig-Burger , C. Thiele , J. Trotter , and of aspartoacylase activity disrupts survival and differentiation of K. A. Nave . 2006 . Perturbed interactions of mutant proteolipid neural progenitors and oligodendrocytes in a mouse model of protein/DM20 with cholesterol and lipid rafts in oligodendroglia: Canavan disease. J. Neurosci. Res. 87 : 3415 – 3427 . implications for dysmyelination in spastic paraplegia. J. Neurosci. 109 . Baslow , M. H. , and D. N. Guilfoyle . 2009 . Are astrocytes the miss- 26 : 11743 – 11752 . ing link between lack of brain aspartoacylase activity and the 131 . Bansal , R. , S. Winkler , and S. Bheddah . 1999 . Negative regula- spongiform leukodystrophy in Canavan disease? Neurochem. Res. tion of oligodendrocyte differentiation by galactosphingolipids. 34 : 1523 – 1534 . J. Neurosci. 19 : 7913 – 7924 . 110 . Verheijen , M. H. , N. Camargo , V. Verdier , K. Nadra , A. S. de 132 . Hirahara , Y. , R. Bansal , K. Honke , K. Ikenaka , and Y. Wada . Preux Charles , J. J. Medard , A. Luoma , M. Crowther , H. Inouye , 2004 . Sulfatide is a negative regulator of oligodendrocyte H. Shimano , et al . 2009 . SCAP is required for timely and proper differentiation: development in sulfatide-null mice. Glia . 45 : myelin membrane synthesis. Proc. Natl. Acad. Sci. USA . 106 : 269 – 277 . 21383 – 21388 . 133 . Nadra , K. , A. S. de Preux Charles , J. J. Medard , W. T. Hendriks , 111 . Lee , A. G. 2003 . Lipid-protein interactions in biological mem- G. S. Han , S. Gres , G. M. Carman , J. S. Saulnier-Blache , M. H. branes: a structural perspective. Biochim. Biophys. Acta . 1612 : 1 – 40 . Verheijen , and R. Chrast . 2008 . Phosphatidic acid mediates demy- 112 . Simons , K. , and W. L. Vaz . 2004 . Model systems, lipid rafts, elination in Lpin1 mutant mice. Genes Dev. 22 : 1647 – 1661 . and cell membranes. Annu. Rev. Biophys. Biomol. Struct. 33 : 134 . Huether , G. , M. Klapproth , and V. Neuhoff . 1986 . Fatty acid co- 269 – 295 . mposition of myelin lipids from developing rat forebrain and Lipids in myelinating glial cells 433 spinal cord: inﬂ uence of experimental hyperphenylalaninaemia. 156 . Das , A. K. , R. D. Holmes , G. N. Wilson , and A. K. Hajra . 1992 . Neurochem. Res. 11 : 1303 – 1311 . Dietary ether lipid incorporation into tissue plasmalogens of hu- 135 . Nave , K. A. 2010 . Myelination and the trophic support of long mans and rodents. Lipids . 27 : 401 – 405 . axons. Natl. Rev. 11 : 275 – 283 . 157 . Saito , K. , V. Dubreuil , Y. Arai , M. Wilsch-Brauninger , D. Schwudke , 136 . Chrast , R. , M. H. Verheijen , and G. Lemke . 2004 . Complement G. Saher , T. Miyata , G. Breier , C. Thiele , A. Shevchenko , et al . factors in adult peripheral nerve: a potential role in energy me- 2009 . Ablation of cholesterol biosynthesis in neural stem cells in- tabolism. Neurochem. Int. 45 : 353 – 359 . creases their VEGF expression and angiogenesis but causes neu- 137 . de Preux , A. S. , K. Goosen , W. Zhang , A. A. Sima , H. Shimano , ron apoptosis. Proc. Natl. Acad. Sci. USA . 106 : 8350 – 8355 . D. M. Ouwens , M. Diamant , J. L. Hillebrands , J. Rozing , G. 158 . Karasinska , J. M. , F. Rinninger , D. Lutjohann , P. Ruddle , S. Lemke , et al . 2007 . SREBP-1c expression in Schwann cells is Franciosi , J. K. Kruit , R. R. Singaraja , V. Hirsch-Reinshagen , J. Fan , affected by diabetes and nutritional status. Mol. Cell. Neurosci. L. R. Brunham , et al . 2009 . Speciﬁ c loss of brain ABCA1 increases 35 : 525 – 534 . brain cholesterol uptake and inﬂ uences neuronal structure and 138 . Verrips , A. , R. A. Wevers , B. G. Van Engelen , A. Keyser , B. G. function. J. Neurosci. 29 : 3579 – 3589 . Wolthers , F. Barkhof , A. Stalenhoef , R. De Graaf , F. Janssen- 159 . Spencer , B. J. , and I. M. Verma . 2007 . Targeted delivery of pro- Zijlstra , A. Van Spreeken , et al . 1999 . Effect of simvastatin in addi- teins across the blood-brain barrier. Proc. Natl. Acad. Sci. USA . 104 : tion to chenodeoxycholic acid in patients with cerebrotendinous 7594 – 7599 . xanthomatosis. Metabolism . 48 : 233 – 238 . 160 . Garbay , B. , F. Boiron-Sargueil , M. Shy , T. Chbihi , H. Jiang , J. 139 . Saheki , A. , T. Terasaki , I. Tamai , and A. Tsuji . 1994 . In vivo and in Kamholz , and C. Cassagne . 1998 . Regulation of oleoyl-CoA syn- vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl thesis in the peripheral nervous system: demonstration of a link coenzyme A (HMG-CoA) reductase inhibitors. Pharm. Res. 11 : with myelin synthesis. J. Neurochem. 71 : 1719 – 1726 . 305 – 311 . 161 . Yao , J. K. , R. T. Holman , M. F. Lubozynski , and P. J. Dyck . 1980 . 140 . Paintlia , A. S. , M. K. Paintlia , M. Khan , T. Vollmer , A. K. Singh , Changes in fatty acid composition of peripheral nerve mye- and I. Singh . 2005 . HMG-CoA reductase inhibitor augments sur- lin in essential fatty acid deﬁ ciency. Arch. Biochem. Biophys. 204 : vival and differentiation of oligodendrocyte progenitors in animal 175 – 180 . model of multiple sclerosis . Faseb. J. 19 : 1407 – 1421 . 162 . Bourre , J. M. , A. Youyou , G. Durand , and G. Pascal . 1987 . Slow 141 . Paintlia , A. S. , M. K. Paintlia , A. K. Singh , and I. Singh . 2008 . recovery of the fatty acid composition of sciatic nerve in rats fed a Inhibition of rho family functions by lovastatin promotes myelin diet initially low in n-3 fatty acids. Lipids . 22 : 535 – 538 . repair in ameliorating experimental autoimmune encephalomy- 163 . Retra , K. , O. B. Bleijerveld , R. A. van Gestel , A. G. Tielens , J. J. elitis. Mol. Pharmacol. 73 : 1381 – 1393 . van Hellemond , and J. F. Brouwers . 2008 . A simple and universal 142 . Stanislaus , R. , A. G. Gilg , A. K. Singh , and I. Singh . 2002 . Immu- method for the separation and identiﬁ cation of phospholipid mo- nomodulation of experimental autoimmune encephalomyelitis lecular species. Rapid Commun. Mass Spectrom. 22 : 1853 – 1862 . in the Lewis rats by Lovastatin. Neurosci. Lett. 333 : 167 – 170 . 164 . Dod , B. J. , and G. M. Gray . 1968 . The lipid composition of rat-liver 143 . Youssef , S. , O. Stuve , J. C. Patarroyo , P. J. Ruiz , J. L. Radosevich , E. plasma membranes. Biochim. Biophys. Acta . 150 : 397 – 404 . M. Hur , M. Bravo , D. J. Mitchell , R. A. Sobel , L. Steinman , and S. 165 . Ray , T. K. , V. P. Skipski , M. Barclay , E. Essner , and F. M. Archibald . S. Zamvil . 2002 . The HMG-CoA reductase inhibitor, atorvastatin, 1969 . Lipid composition of rat liver plasma membranes. J. Biol. promotes a Th2 bias and reverses paralysis in central nervous sys- Chem. 244 : 5528 – 5536 . tem autoimmune disease. Nature. 420 : 78 – 84 . 166 . Lorincz , M. T. , S. Rainier , D. Thomas , and J. K. Fink . 2005 . Cere- 144 . Sena , A. , R. Pedrosa , and M. Graca Morais . 2003 . Therapeutic po- brotendinous xanthomatosis: possible higher prevalence than tential of lovastatin in multiple sclerosis. J. Neurol. 250 : 754 – 755 . previously recognized. Arch. Neurol. 62 : 1459 – 1463 . 145 . Vollmer , T. , L. Key , V. Durkalski , W. Tyor , J. Corboy , S. Markovic- 167 . Brunham , L. R. , R. R. Singaraja , and M. R. Hayden . 2006 . Vari- Plese , J. Preiningerova , M. Rizzo , and I. Singh . 2004 . Oral simvas- ations on a gene: rare and common variants in ABCA1 and their tatin treatment in relapsing-remitting multiple sclerosis . Lancet. impact on HDL cholesterol levels and atherosclerosis. Annu. Rev. 363 : 1607 – 1608 . Nutr. 26 : 105 – 129 . 146 . Maier , O. , J. De Jonge , A. Nomden , D. Hoekstra , and W. Baron . 168 . Heim , P. , M. Claussen , B. Hoffmann , E. Conzelmann , J. Gartner , 2009 . Lovastatin induces the formation of abnormal myelin- K. Harzer , D. H. Hunneman , W. Kohler , G. Kurlemann , and A. like membrane sheets in primary oligodendrocytes. Glia . 57 : Kohlschutter . 1997 . Leukodystrophy incidence in Germany. Am. 402 – 413 . J. Med. Genet. 71 : 475 – 478 . 147 . Gaist , D. , U. Jeppesen , M. Andersen , L. A. Garcia Rodriguez , J. 169 . Gustavson , K. H. , and B. Hagberg . 1971 . The incidence and ge- Hallas , and S. H. Sindrup . 2002 . Statins and risk of polyneuropa- netics of metachromatic leucodystrophy in northern Sweden. Acta thy: a case-control study. Neurology . 58 : 1333 – 1337 . Paediatr. Scand. 60 : 585 – 590 . 148 . Law , M. , and A. R. Rudnicka . 2006 . Statin safety: a systematic re- 170 . Schuchman , E. H. 2007 . The pathogenesis and treatment of view. Am. J. Cardiol. 97 : 52C – 60C . acid sphingomyelinase-deﬁ cient Niemann-Pick disease. J. Inherit. 149 . Brown , W. V. 2008 . Safety of statins. Curr. Opin. Lipidol. 19 : Metab. Dis. 30 : 654 – 663 . 558 – 562 . 171 . Jagell , S. , K. H. Gustavson , and G. Holmgren . 1981 . Sjogren- 150 . Verhave , P. S. , R. A. Vanwersch , H. P. van Helden , A. B. Smit , and Larsson syndrome in Sweden. A clinical, genetic and epidemio- I. H. Philippens . 2009 . Two new test methods to quantify motor logical study. Clin. Genet. 19 : 233 – 256 . deﬁ cits in a marmoset model for Parkinson’s disease. Behav. Brain 172 . Lazarow , P. B. , and H. W. Moser . 1989 . Disorders of peroxisome Res. 200 : 214 – 219 . biogenesis. In The Metabolic Basis of Inherited Disease. C. R. 151 . Jurevics , H. A. , and P. Morell . 1994 . Sources of cholesterol for Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, editors. McGraw- kidney and nerve during development. J. Lipid Res. 35 : 112 – 120 . Hill, New York. 1479–1509. 152 . Morell , P. , and H. Jurevics . 1996 . Origin of cholesterol in myelin. 173 . Berger , J. , and J. Gartner . 2006 . X-linked adrenoleukodystrophy: Neurochem. Res. 21 : 463 – 470 . clinical, biochemical and pathogenetic aspects. Biochim. Biophys. 153 . Kelley , R. I. 2000 . Inborn errors of cholesterol biosynthesis. Adv. Acta . 1763 : 1721 – 1732 . Pediatr. 47 : 1 – 53 . 174 . Feigenbaum , A. , R. Moore , J. Clarke , S. Hewson , D. Chitayat , P. N. 154 . Ullrich , K. , H. G. Koch , D. Meschede , U. Flotmann , and U. Ray , and T. L. Stockley . 2004 . Canavan disease: carrier-frequency Seedorf . 1996 . Smith-Lemli-Opitz syndrome: treatment with cho- determination in the Ashkenazi Jewish population and develop- lesterol and bile acids. Neuropediatrics . 27 : 111 – 112 . ment of a novel molecular diagnostic assay. Am. J. Med. Genet. A. 155 . Arun , P. , C. N. Madhavarao , J. R. Moffett , K. Hamilton , N. E. 124A : 142 – 147 . Grunberg , P. S. Ariyannur , W. A. Gahl , Y. Anikster , S. Mog , W. C. 175 . Brun , N. , Y. Robitaille , A. Grignon , B. H. Robinson , G. A. Mitchell , Hallows , et al . 2010 . Metabolic acetate therapy improves pheno- and M. Lambert . 1999 . Pyruvate carboxylase deﬁ ciency: prenatal type in the tremor rat model of Canavan disease. J. Inherit. Metab. onset of ischemia-like brain lesions in two sibs with the acute neo- Dis. 33 : 195 – 210 . natal form. Am. J. Med. Genet. 84 : 94 – 101 . 434 Journal of Lipid Research Volume 52, 2011 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Lipid Research American Society for Biochemistry and Molecular Biology http://www.deepdyve.com/lp/american-society-for-biochemistry-and-molecular-biology/lipid-metabolism-in-myelinating-glial-cells-lessons-from-human-p1AyVEgrsL

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Publisher: American Society for Biochemistry and Molecular Biology
Copyright: Copyright © 2011 Elsevier Inc.
ISSN: 0022-2275
eISSN: 1539-7262
DOI: 10.1194/jlr.r009761
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Abstract

thematic review Thematic Review Series: Genetics of Human Lipid Diseases Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models 1, † † 1,§ Roman Chrast , * Gesine Saher , Klaus-Armin Nave , and Mark H. G. Verheijen Department of Medical Genetics,* University of Lausanne , Switzerland; Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine , Goettingen, Germany; and Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands Abstract The integrity of central and peripheral nervous and Schwann cells in the peripheral nervous system (PNS) system myelin is affected in numerous lipid metabolism dis- ( Fig. 1 ). The wrapping of myelin around an axonal seg- orders. This vulnerability was so far mostly attributed to the ment increases axonal resistance and enables clustering of extraordinarily high level of lipid synthesis that is required axonal ion channels at nodes of Ranvier ( 1 ). As such, my- for the formation of myelin, and to the relative autonomy in elinating glial cells shape the structural and electrical lipid synthesis of myelinating glial cells because of blood properties of axons resulting in a 10- to 100-fold increase barriers shielding the nervous system from circulating lip- in nerve conduction velocity ( 2, 3 ) and in a great reduc- ids. Recent insights from analysis of inherited lipid disor- tion of axonal energy consumption ( 4 ). ders, especially those with prevailing lipid depletion and from mouse models with glia-speciﬁ c disruption of lipid One of the prominent biochemical characteristics that metabolism, shed new light on this issue. The particular distinguishes myelin from other membranes is its high lipid composition of myelin, the transport of lipid-associated lipid-to-protein ratio; lipids account for at least 70% of the myelin proteins, and the necessity for timely assembly of the dry weight of myelin membranes ( Table 1 ) , which is also myelin sheath all contribute to the observed vulnerability the physical basis for its biochemical puriﬁ cation by su- of myelin to perturbed lipid metabolism. Furthermore, the crose gradient centrifugation ( 5 ). uptake of external lipids may also play a role in the forma- The myelin membrane contains myelin-speciﬁ c proteins tion of myelin membranes. In addition to an improved (e.g., myelin basic protein, myelin-associated glycopro- understanding of basic myelin biology, these data provide tein, and proteolipid protein), but no truly myelin-speciﬁ c a foundation for future therapeutic interventions aiming at preserving glial cell integrity in metabolic disorders. — lipids. Nevertheless, whereas all major lipid classes are Chrast, R., G. Saher, K-A. Nave, and M. H. G. Verheijen. present in myelin as in other membranes, myelin has its Lipid metabolism in myelinating glial cells: lessons from hu- characteristic lipid composition. The myelin membrane man inherited disorders and mouse models. J. Lipid Res . contains a high level of cholesterol of at least 26% by 2011. 52: 419–434. weight (or 52 mol%) ( Table 1 ) ( 6, 7 ). The importance of cholesterol for myelin production and maintenance has recently been reviewed ( 8 ). The myelin membrane is also MYELIN: A GIANT MEMBRANE ORGANELLE WITH substantially enriched in galactolipids (31% vs. 7% for SPECIFIC LIPID CHARACTERISTICS liver cell plasma membranes). Two glycosphingolipids, The rapid saltatory conduction of action potentials along axons is crucially dependent on myelination. The myelin membrane is an extended and highly specialized Abbreviations: ALD, adrenoleukodystrophy; ASPA, aspartoacylase; plasma membrane synthesized by myelinating glial cells: CD, Canavan disease; CGT, ceramide galactosyltransferase; CNS, cen- oligodendrocytes in the central nervous system (CNS), tral nervous system; CST, cerebroside sulfotransferase; CTX, Cerebro- tendinous xanthomatosis ; DHCR7, delta-7-reductase; FA2H, fatty acid 2-hydroxylase; HFA, hydroxyl fatty acid; NAA, N-acetylaspartic acid; OL, oligodendrocyte; PA, phosphatidic acid; PCD, pyruvate carboxyl- This work is supported by the European Union Grant EU-NEST 12702 (to ase deﬁ ciency; PLP, proteolipid protein; PNS, peripheral nervous sys- M.H.G.V.), Swiss National Science Foundation Grant PP00P3-124833/1 (to tem; RD, Refsum disease; SCAP, SREBP cleavage activating protein; R.C.), Deutsche Forschungsgemeinschaft (CMPB, to K-A.N.), and EU-FP7 SLOS, Smith-Lemli-Opitz syndrome; SREBP, sterol regulatory element- (NGIDD, Leukotreat, to K-A.N.). binding protein; SQS, squalene synthase; TD, Tangier disease; VLCFA, Manuscript received 9 July 2010 and in revised form 9 November 2010. very long-chain fatty acid. To whom correspondence should be addressed. Published, JLR Papers in Press, November 9, 2010 e-mail: [email protected]; [email protected] DOI 10.1194/jlr.R009761 Copyright © 2011 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr.org Journal of Lipid Research Volume 52, 2011 419 This is an Open Access article under the CC BY license. Fig. 1. Ultrastructural comparison of the mem- branes of a promyelinating versus a mature myelinat- ing glial cell. Electron micrographs of normal mouse sciatic nerves showing (A) promyelin ﬁ gure at postna- tal day 0 (P0) and (B) adult myelinated ﬁ ber (P100). The inner lip (also called inner mesaxon) of the my- elinating glial cell, which turns around the axon to form the membranous spiral of myelin, is depicted with an asterisk (*). Scale bar, 0.5 m. Sciatic nerve isolation and electron microscopy were done as de- scribed in ( 110 ). the monogalactosylsphingolipids cerebroside and sul- month) and is followed by myelination of the spinal cord fatide account for 14%–26% and 2%–7% of myelin lipids, and brain (CNS). The majority of myelin is assembled dur- respectively ( 9–11 ). When compared with hepatocyte and ing the ﬁ rst two years of postnatal life ( 14 ), but myelina- erythrocyte membranes, myelin membranes also contain a tion continues for 2–3 decades in the human cerebral higher proportion of saturated long-chain fatty acids ( Fig. white matter ( 15, 16 ). In rodents, myelination occurs pre- 2 ). Finally, the lipid content of myelin is also enriched in dominantly during the ﬁ rst month of life ( 17 ). The magni- plasmalogens (etherlipids). These glycerophospholipids, tude of the tasks that glial cells have to accomplish in a deﬁ ned by a vinyl ether double bond at the sn-1 position, short period of time is easily appreciated when visualizing account for 20% of the myelin phospholipid mass (com- the membrane expansion taking place during myelination pared with 18% in the average human phospholipid mass). ( Fig. 1 ). In rodents, it has been estimated that the myelin- Here, 70% of the total phosphatidylethanolamine in white membrane surface area of one glial cell expands at a rate 3 2 matter is plasmalogen, in contrast to only 5% in liver ( 12, of 5–50 × 10 m /day, compared with the surface area of 13 ). These lipid characteristics of myelin, together with the cell soma (i.e., the plasma membrane) of 0.3 × 10 the presence of myelin-speciﬁ c proteins, are likely re- m ( 18 ). This corresponds to an estimated 6,500-fold in- quired for myelin wrapping and/or to confer the speciﬁ c crease in membrane surface between an immature and a biophysical properties of myelin as an electrical “insula- fully myelinated oligodendrocyte ( 19 ). In rodents, the ex- tor”, as will be discussed below. pansion of the myelin membrane correlates with substan- During development of the human nervous system, my- tial accumulation of cholesterol and lipids in both the elination starts in the motor roots of the PNS (ﬁ fth fetal developing CNS and PNS ( 17, 20–22 ). More recently, tran- scriptional proﬁ ling of developing peripheral nerves shed light on the molecular cascades involved in PNS myelin assembly ( 23, 24 ). It was observed that transcripts encod- TABLE 1. Approximate lipid composition of the myelin membrane ing structural myelin proteins and enzymes involved in Liver Cell a b myelin lipid biosynthesis were expressed in a highly syn- Myelin Membrane Plasma Membrane chronized and timely fashion, suggesting a strict control of Lipid content (dry weight) 71% 34% a balanced and local production of these two key compo- Lipid class nents of myelin assembly. Relatively little is known about Cholesterol 26% 17% Phospholipids myelin lipid turnover in vivo, but studies in mice indicate PE 16% 7% a necessity to renew myelin lipids in adult life ( 25 ). PS 6% 4% PC 12% 24% PI 1% 4 SM 3% 20% MYELIN DEFECTS IN INHERITED DISEASES Glycolipids 31% 7% AFFECTING LIPID METABOLISM Other lipids 5% 17% From Norton and Poduslo 1973 ( 6 ): myelin of adult rat brain. The lipid-rich composition of myelin is likely to contrib- Comparable lipid amounts are present in myelin of rodent peripheral ute to the frequent occurrence of myelin defects in lipid nerve, with the exception of much higher SM levels (10–35%) ( 7 ). metabolism disorders, including hypomyelination (decreased From Dod and Gray, 1968 ( 164 ): plasma membrane of adult rat liver. The category ‘other lipids’ contains free fatty acids, triglycerides myelin production), dysmyelination (abnormally formed and cholesterol esters, which could be indicative for contamination by myelin), and demyelination (degenerative loss of myelin). other membranes. Comparable lipid amounts were found by Ray et al., Inherited forms of these diseases are particularly informa- 1968 ( 165 ). Bold numbers indicate percentages of lipids enriched in myelin, as discussed in the text. tive and provide direct insight into the underlying molecu- 420 Journal of Lipid Research Volume 52, 2011 Fig. 2. Fatty acid composition of myelin compared with other membranes. Depicted is the amount of fatty acid in mol percentage of total amount of fatty acids. Bold numbered and gray numbered lipids depict, re- spectively, strongly higher or lower levels of these fatty acids in myelin compared with hepatocytes or eryth- rocyte membranes. Myelin membrane of mouse sciatic nerve were isolated as described in ( 110, 163 ). Mouse erythrocyte membranes and hepatocyte phospholipids were isolated and analyzed according to ( 110, 163 ). It should be noted that under the isolation conditions used, amide bonds in sphingolipids are relatively stable. Hence, the very long-chain fatty acids found in myelin are not reﬂ ecting the high level of galactosphingolip- ids in myelin, but are more likely to result from a particular fatty acyl composition of the glycerophospho- lipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine). In addition, with the detection method used, the bar representing 18:1 fatty acids does not include 18:1 alcohol of plasmalogens, which nevertheless was previously detected to be very low in PNS myelin in mouse ( 110 ). lar mechanisms. These involve defects in metabolism of all CNS defects in white matter are common, often involving myelin enriched lipids: cholesterol, glycosphingolipid, corpus callosum absence or hypoplasia ( 36–42 ), and re- and long-chain fatty acids ( Table 2 ). In several of these ported to involve absence of myelin ( 42 ) and demyeli- disorders the defects are caused by lipotoxicity, a result of nation ( 43 ), but detailed analysis of myelin structure has the accumulation of various metabolic precursors involved not yet been described. The relative contribution of ei- in lipid biosynthesis to levels that are toxic to the myelin- ther cholesterol depletion or 7-dehydro-cholesterol and ating glial cells or at least interfere with normal myelin 8-dehydro-cholesterol accumulation in white matter ab- membrane structure [reviewed in ( 26–28 )]. Here, we will normalities is currently unclear. Interestingly, dietary cho- particularly discuss the disorders in which myelin defects lesterol supplementation has become the standard therapy are more likely caused by a primary defect in myelinating for SLOS and was reported to partially improve the neuro- glia that causes reduced levels of myelin-enriched lipids, logical status and white matter lipid abnormalities in some and are therefore more informative as to the contribution patients ( 36, 44–46 ). Remarkably, PNS myelin defects are of these lipids to the synthesis and function of myelin un- rarely reported for SLOS. The reason for this is currently der normal and pathological conditions (see section ‘Why unclear, but dietary lipid supplementation has also been are myelinating glial cells particularly vulnerable to lipid reported to improve a case of SLOS-associated demyelinat- metabolism disorders?’). ing polyneuropathy ( 47 ). Cholesterol disorders Mouse models of cholesterol disorders. Multiple mouse At least three different cholesterol-related disorders models of SLOS recapitulate morphological and biochem- cause defects in myelin ( Table 2 ). Of these, Cerebrotendi- ical aspects of the neuropathology of SLOS patients nous xanthomatosis (CTX) and Tangier disease (TD) lead ( 48–50 ). Although ventricular dilatation and partial agen- to accumulation of 7 -hydroxy-4-cholesten-3-one and cho- esis of corpus callosum was observed in one of these mod- lestanol (in CTX) and cholesterolesters (in TD), which els ( 50 ), the status of myelination was so far not analyzed are likely to underlie the myelin pathology [( 29–32 ), Fig. in DHCR7 mutant animals. The importance of local cho- 3 ] . Myelin defects due to reduced cholesterol levels are lesterol biosynthesis in myelinating glial cells was, however, possibly found in Smith-Lemli-Opitz syndrome (SLOS), addressed by conditional inactivation of squalene synthase which is caused by mutations in the gene encoding sterol (SQS; gene symbol fdft1 ) speciﬁ cally in oligodendrocytes ﬂ ox/ﬂ ox +/cre delta-7-reductase (DHCR7), the enzyme catalyzing the last and Schwann cells of fdft /cnp1 mice ( 51, 52 ) in step of cholesterol biosynthesis. This results in the eleva- which expression of cre recombinase (cre) was under con- tion of the cholesterol precursors 7-dehydro-cholesterol trol of the 2’:3 ′ -cyclic nucleotide 3 ′ -phosphodiesterase and 8-dehydro-cholesterol and in cholesterol deﬁ ciency in (cnp) promoter. In the CNS, SQS inactivation led to sub- all tissues ( 33–35 ). Patients with SLOS have multiple mal- stantial hypomyelination and reduced motor performance formations, cognitive impairment, and behavioral deﬁ cits. in 20-day-old SQS conditional mutants. The discrepancy Lipids in myelinating glial cells 421 422 Journal of Lipid Research Volume 52, 2011 TABLE 2. Inherited lipid disorders with myelin abnormalities Presumed Incidence or Myelin Defect Number of General Clinical Disease OMIM# Inheritance Patients Mutated Gene Function Features Onset CNS PNS Remarks Smith-Lemli-Opitz 270400 Autosomal 1-2:40,000 sterol delta-7-reductase cholesterol microcephaly mental mostly within the ﬁ rst ++ + - absence or syndrome recessive metabolism retardation hypotonia month of life hypoplasia of micrognathia polydactyly (early lethality corpus callosum ambiguous genitalia is common) detected cleft palate - reduced NCV in PNS (rare) Cerebrotendinous 213700 Autosomal 1:50,000 ( 166 ) sterol 27-hydroxylase cholesterol tendon xanthomas mental variable (6 to 60 years) ++ ++ - diffuse or focal xanthomatosis recessive metabolism retardation cerebellar cerebral and ataxia spasticity cataracts cerebellar white matter disease detected - reduced NCV in PNS Tangier disease 205400 Autosomal 100 patients ( 167 ) ATP-binding cassette cholesterol yellow-orange tonsils variable (2 to 67 years) +++ - PNS diagnostics: recessive transporter A1 transport splenomegaly neuromuscular hepatomegaly peripheral symptoms, neuropathy mostly normal NCV Dysmyelinating 612443 Autosomal 5 families ( 58 ) fatty acid 2-hydroxylase sphingolipid spasticity gait difﬁ culties 4 to 11 years + - hyperintensities leukodystrophy and recessive metabolism dystonia cognitive decline in parietal and spastic paraparesis occipital white with or without dystonia matter were detected Metachromatic 250100 Autosomal 0.6-2,5:100,000 arylsulfatase A sphingolipid ataxia variable (late infantile +++ +++ - hyperintensities leukodystrophy recessive ( 168, 169 ) metabolism muscle weakness to adult onset) detected in optic atrophy white matter mental deterioration - reduced NCV in white matter abnormalities PNS peripheral neuropathy Krabbe disease 245200 Autosomal 1:100,000 galactosylceramidase sphingolipid developmental regression variable, but 90% +++ +++ - diffuse cerebral recessive metabolism hyperirritability within ﬁ rst 6 months atrophy detected seizures of life (in this case - reduced NCV in optic atrophy the lethality before PNS the age of 2 years is common) Niemann-Pick disease 257200 Autosomal 0.5-1:100,000 (general sphingomyelin sphingolipid cherry-red maculae early onset (infancy) +++ + - reduced NCV in type A recessive population) phosphodiesterase-1 metabolism hepatomegaly xanthomas lethality before the PNS 3:100,000 (Ashkenazi muscle weakness age of 3 years Jews) ( 170 ) psychomotor retardation is common large vacuolated foam cells Sjogren-Larsson syndrome 270200 Autosomal 0.6:100,000 fatty aldehyde fatty acid spasticity mental retardation neurologic symptoms ++ - hyperintensities recessive in Sweden ( 171 ) dehydrogenase metabolism macular degeneration usually develop detected in short stature within 2 years white matter enamel hypoplasia after birth Peroxisome biogenesis 214100 Autosomal 1:100,000 peroxin 1 to 12 fatty acid facial dysmorphism lethality before the age +++ + - colpocephaly disorder recessive in USA ( 172 ) metabolism severe mental retardation of 1 year is common and mild plasmalogen hypotonia seizures impairment of synthesis hyporeﬂ exia/areﬂ exia myelination hepatomegaly detected Fig. 3. Human inherited and mouse experimental defects in the cholesterol biosynthesis pathway that cause myelin disorders. Solid line arrows depict a direct link between two steps, dashed line ar- rows imply intermediate steps that are not shown. Dark gray ovals show the positions of human disease genes; light gray oval shows the position of mutated genes in experimental mouse models. Sqs, squalene synthase; DHCR7, sterol delta-7-reductase; SLOS, Smith-Lemli-Opitz syndrome; CYP27A1, sterol 27-hydroxylase; CTX, Cerebrotendinous xanthomatosis; ABC1, ATP-binding cas- sette transporter A1; TD, Tangier disease. between the robust hypomyelination observed in SQS mouse mutants and the mild myelin defects observed in human SLOS is unclear, but may be related to the low amounts of cholesterol that are still produced in some forms of SLOS ( 33 ) and/or to the position of the defects leading to disruption of the cholesterol biosynthesis path- way, which is more upstream in SQS mouse mutants. Whereas the amount of myelin in SQS conditional mu- tants was decreased, its ultrastructure, lipid, and protein composition were not affected, suggesting a tight control mechanism matching the amount of myelin proteins pro- duced by glial cells to the available cholesterol. Interest- ingly, both hypomyelination and motor deﬁ cits improved over time. These observations suggest that cell autono- mous synthesis of cholesterol in oligodendrocytes is cru- cial for normal onset and progression of myelination. Cholesterol biosynthesis-deﬁ cient oligodendrocytes are, however, able to take up some cholesterol from their sur- rounding for limited myelin formation ( 51 ). The exact mechanism of this horizontal cholesterol transfer remains to be clariﬁ ed. In the PNS, the inactivation of cholesterol biosynthesis in Schwann cells also led to substantial hypo- myelination as detected by morphometric analysis of sciatic ﬂ ox/ﬂ ox +/cre nerves from fdft /cnp1 animals. Similar to oligo- dendrocytes, also Schwann cells are able to take up extra- cellular cholesterol because many axons in peripheral ﬂ ox/ﬂ ox +/cre nerves from fdft /cnp1 animals are ensheathed Lipids in myelinating glial cells 423 TABLE 2. Continued. Presumed Incidence or Myelin Defect Number of General Clinical Disease OMIM# Inheritance Patients Mutated Gene Function Features Onset CNS PNS Remarks Refsum disease 266500 Autosomal unknown phytanoyl-CoA fatty acid retinitis pigmentosa majority 20 to 30 years + ++ - white matter recessive hydroxylase metabolism peripheral neuropathy changes cerebellar ataxia deafness detected - reduced NCV in PNS Adrenoleukodystrophy 300100 X-linked 1:42,000 ( 173 ) ATP-binding cassette fatty acid adrenal insufﬁ ciency 7 to 20 years +++ + - white matter transporter D1 metabolism neurodegeneration changes blindness hearing loss detected spastic paraplegia paraparesis Canavan disease 271900 Autosomal generally rare aspartoacylase lipogenesis atonia of neck 2 to 4 months (death +++ - white matter recessive 1:13,000 in muscles hypotonia within ﬁ rst decade) changes Ashkenazi seizures blindness detected Jews ( 174 ) severe mental defect Pyruvate carboxylase 266150 Autosomal 1:250,000 ( 175 ) pyruvate carboxylase lipogenesis hepatomegaly mental Onset at birth or in early +++ - white matter deﬁ ciency recessive gene retardation psychomotor infancy changes retardation lactic acidemia detected Information provided is based on OMIM database (www.ncbi.nlm.nih.gov/omim/), additional references on presumed incidence, and references on myelin defects as provided in the text. by (albeit thin) myelin. These data have been corrobo- both galactosylceramides and sulfatides contain high pro- rated by in vitro experiments showing that extracellular portions (up to 50%) of 2-hydroxy fatty acids ( 59 ). Surpris- cholesterol increased myelination in both wild-type and ingly, the FA2H mutations result in demyelination of the mutant Schwann cells ( 52 ). Interestingly, detailed ultra- CNS, whereas PNS myelin abnormalities are not found, structural and biochemical analysis of mutant myelin re- suggesting there is a second fatty acid 2-hydroxylating ac- vealed substantial increase in the amount of noncompact tivity in human Schwann cells ( 57 ). myelin, probably as a consequence of defective myelin protein transport from the endoplasmic reticulum to the Mouse models of glycosphingolipid disorders. FA2H deﬁ - myelin sheath (see below). These data, together with a syn- cient mouse mutants lack 2-hydroxylated sphingolipids chronized downregulation of the mRNA expression for [hydroxyl fatty acid (HFA)-GalC and HFA-sulfatide] as multiple myelin proteins, suggest that in addition to its evaluated by thin-layer chromatography and MALDI-time- role as a major structural component of myelin, choles- of-ﬂ ight (TOF) MS ( 60 ). The absence of 2-hydroxylated terol plays a crucial role in coordinating myelin membrane sphingolipids in mice does not cause any detectable my- assembly. elin changes up to adulthood. However, myelin decom- paction was detected in aged (18 months) brain and was Glycosphingolipid disorders even more severe in peripheral nerve samples where signs Most of the myelin defects in glycosphingolipid disor- of myelin degeneration (e.g., decompaction and myelin ders are due to accumulation of glycosphingolipids or loss) were observed, clearly suggesting a role of HFAs in their precursors ( Table 2 ). Metachromatic leukodystro- long-term myelin stability. The presence of this discrete phy, Krabbe disease, and Niemann-Pick disease type A phenotype, or its late onset, suggests the possibility that lead to the accumulation of respectively sulfatides, galac- other models of glycosphingolipid disorders, including a tocerebrosides (and sphingosine), and sphingomyelin mouse model of Gaucher disease ( 61 ) or a knockout mouse [( 53–56 ) Fig. 4 ) . The accumulation of these lipids in my- for sphingomyelin synthase 2 ( 62 ), may have ultrastruc- elinating glial cells leads predominantly to cytotoxicity tural myelin changes that so far have not been detected. and demyelination. Myelin defects present in dysmyelinat- The role of the most abundant galactosphingolipids in ing leukodystrophy and spastic paraparesis with or without myelin was analyzed in mouse models disrupting either dystonia ( 57, 58 ), which is caused by a mutation in the sulfatide biosynthesis alone [cerebroside sulfotransferase gene encoding fatty acid 2-hydroxylase (FA2H), are, how- (CST) knockout mice] or disrupting both galactocerebro- ever, probably a consequence of reduced glycosphingo- side and sulfatide biosynthesis [UDP-galactose:ceramide lipid levels. The 2-hydroxylation of sphingolipid N -acyl galactosyltransferase (CGT) knockout mice, Fig. 4 ]. Char- chains catalyzed by the FA2H occurs during de novo cer- acterization of CST-deﬁ cient mice revealed that sulfatide amide synthesis. In accordance with the high level of FA2H plays a crucial role in maintenance of myelin structure and in mammalian central and peripheral nervous systems, organization of node and paranode ( 63, 64 ). Interestingly, whereas apparently normal myelin can be assembled in CST mutant animals, the myelin structure is disturbed with age, as reﬂ ected by uncompacted myelin sheaths in the CNS and nodal and paranodal abnormalities in both the CNS and PNS. The defective sulfatide biosynthesis also leads to axonal changes, as demonstrated by the loss of large axons in the CNS and the presence of axonal protru- sions in the PNS. In comparison, CGT mutant animals, which are unable to synthesize both galactocerebroside and sulfatide, have a similar but more marked myelin phe- notype because myelin abnormalities (including uncom- pacted areas and redundant myelin proﬁ les) are already present at P10 and evolve to substantial demyelination at / / P43 ( 65 ). Both CGT and CST animals develop a Fig. 4. Human inherited and mouse experimental defects in the glycosphingolipids synthesis pathway that cause myelin disorders. similar nodal phenotype characterized by disorganized para- Solid line arrows depict direct link between two steps, dashed line nodal loops and enlarged nodal gaps ( 63 ). Because the arrow implies intermediate steps that are not shown. Dark gray CGT animals accumulate HFA-Glc-Cer (which is nor- ovals show positions of human diseases; light gray ovals show the mally absent) in their myelin, it was suggested that HFA- position of mutated genes in experimental mouse models. ARSA, Glc-Cer could compensate partially for the absence of arylsulfatase A; ML, Metachromatic leukodystrophy; Cst, cerebro- galactolipids in these animals. However, inactivation of side sulfotransferase; GALC, galactosylceramidase; KD, Krabbe disease; Cgt, UDP-galactose:ceramide galactosyltransferase; Ugcg, UDP-glucose ceramide glucosyltransferase (Ugcg), which UDP-glucose ceramide glucosyltransferase; SMPD1, sphingomyelin prevented accumulation of HFA-Glc-Cer, did not lead to phosphodiesterase-1; NPD, Niemann-Pick disease type A; FA2H, any aggravation of myelin phenotype in double knockout fatty acid 2-hydroxylase; DLSP, Dysmyelinating leukodystrophy and ﬂ ox/ﬂ ox / Ugcg ; Cnp/Cre; CGT mice ( 66 ). These data there- spastic paraparesis with or without dystonia; Gal-Cer, galactocere- fore suggest that glial cells are able to assemble myelin in broside; Glc-Cer: glucocerebroside; 2-OH FA, 2-hydroxy fatty acids; the absence of glycolipids. FA, fatty acids. 424 Journal of Lipid Research Volume 52, 2011 Fig. 5. Human inherited and mouse experimental defects in fatty acids and plasmalogen metabolism that cause myelin disorders. Solid line arrows depict direct link between two steps, dashed line arrow im- plies intermediate steps that are not shown. Dashed line rectangles represent various lipid metabolic path- ways in the peroxisome. Dark gray ovals show posi- tions of human disease genes; light gray ovals show the position of mutated genes in experimental mouse models. Dhapat, dihydroxyacetone phosphate acyl- transferase; PHYH, phytanoyl-CoA hydroxylase; RD, Refsum disease; PEX1-12, peroxins; PBD, peroxisome biogenesis disorders; ALDH3A2, fatty aldehyde dehy- drogenase; SLS, Sjogren-Larsson syndrome; ABCD1, ATP-binding cassette transporter D1; ALD, adreno- leukodystrophy; VLCFA, very long-chain fatty acids. Fatty acid and plasmalogen disorders panied by progressive loss of CNS and PNS myelin levels from early adulthood on and dysmyelination predomi- S everal disorders in fatty acid metabolism are associated nantly in the PNS. It remains to be determined whether with defects in myelin that are mostly caused by the accu- myelinating glial cells are the primary cause, but these mulation of lipids ( Table 2 , Fig. 5 ). In Sjogren-Larsson data are indicative of the involvement of VLCFA in main- syndrome (SLS) mutations in fatty aldehyde dehydroge- tenance of the myelin membrane ( 75 ). nase result in the accumulation of long-chain fatty alco- Several mouse models have been generated for differ- hols ( 67 ), leading to CNS white matter abnormalities that ent peroxisomal disorders. Many of those recapitulate the are related to dysmyelination and hypomyelination ( 68, main pathological or biochemical defects observed in pa- 69 ). Lipid accumulation is also found in peroxisome tients, most often associated with lipotoxicity caused by disorders, such as Refsum disease [RD ( 70 )], adrenoleu- accumulation of metabolic intermediates, like VLCFA in kodystrophy [ALD ( 53 )], and peroxisome biogenesis RD and in ALD ( 76–81 ). It should be noted that satu- disorders ( 71 ). In RD, mutation of phytanoyl-CoA hydrox- rated VLCFAs, which are enriched in myelin ( Fig. 2 ), rely ylase leads to the accumulation of phytanic acid, a plant- fully on peroxisomes for -oxidation, which could under- derived fatty acid that is normally degraded by -oxidation lie the vulnerability of myelin for VLCFA accumulation in in peroxisomes. Accumulation of phytanic acid causes de- these disorders. Peroxisome biogenesis disorders have myelination, especially in the PNS. ALD is caused by muta- been modeled by inactivating different Pex genes (Pex2, tion of the ABCD1 protein which functions as a transporter Pex5, Pex13), which resulted in an early postnatal death of for the uptake of very long-chain fatty acids (VLCFAs) in affected animals, preventing myelin analysis ( 78–81 ). Mice peroxisomes. Because VLCFAs are metabolized in peroxi- carrying an oligodendrocyte speciﬁ c deletion of Pex 5 somes via -oxidation, myelinating glial cells in ALD- (CNPcre-Pex5 ( 82 )) assembled normal myelin, but sur- patients accumulate VLCFA, which causes dysmyelination prisingly within a few months, developed axonal defects but also inﬂ ammatory-induced demyelination. The latter followed by inﬂ ammatory demyelination. The observation may be caused by the failure to degrade arachidonic acid- that the PEX5-deﬁ cient oligodendrocytes are not able to derived eicosanoids ( 72, 73 ). Peroxisome biogenesis disor- maintain axonal integrity, even in the absence of obvious ders of Zellweger syndrome occur when any one of 12 demyelination, indicates a role of oligodendrocyte peroxi- peroxins involved in the import of peroxisomal proteins is some-associated lipid metabolism in axonal support. In mutated [for a recent review, see ( 74 )]. The consequent addition, the remarkable inﬂ ammatory demyelination ob- partial or complete peroxisome dysfunction results in de- served in CNPcre-Pex5 mice suggest a role for abnormal fective - and -oxidation, subsequent accumulation of lipid metabolism in inﬂ ammation ( 82 ), as also observed in fatty acids, leading to myelin defects as also seen in ALD or human ALD disease ( 72, 83, 84 ). Interestingly, polyunsat- RD. In addition, myelin defects due to reduced lipid levels urated VLCFAs, such as arachidonic acid, are substrates are found in Zellweger syndrome as well, because the per- for the synthesis of eicosanoids, which are lipid inﬂ amma- oxisomal anabolic lipid pathway involved in ether lipid tory mediators ( 85, 86 ). Peroxisomes play a major role in synthesis is disrupted ( Fig. 5 ), resulting in plasmalogen de- the degradation of eicosanoids ( 72, 87, 88 ). The fact that ﬁ ciency and consequent mild hypomyelination and dys- the VLCFAs in myelin are saturated and not unsaturated myelination, especially in the CNS. might reduce the risk of generating too high levels of lipid Mouse models of fatty acid disorders. As shown in Fig. 2 , inﬂ ammatory mediators. Together, these data suggest that myelin is speciﬁ cally enriched in saturated VLCFAs (C22:0- peroxisomes in myelinating glial cells are likely to be im- portant for protection against lipid induced inﬂ ammation, C24:0). Mice carrying a deletion of ceramide synthase 2, by degrading VLCFA and eicosanoids. The observations an enzyme that is mostly involved in synthesis of ceramides with VLCFAs, show myelin with ceramide species that no on CNP-cre-PEX5 mice furthermore indicate that peroxi- longer have VLCFAs ( C22) but instead are enriched in some-associated lipid metabolism is not required in oligo- dendrocytes for myelin membrane synthesis per se. However, short-chain fatty acids ( 75 ). These changes where accom- Lipids in myelinating glial cells 425 mice in which Pex5 is lacking in all neural cells [Nestin-cre PEX5 mice ( 80 )] do show dysmyelination, indicating that, in CNP-cre-PEX5 mice, oligodendrocytes may take up per- oxisome-derived lipids from other neural cells and utilize these lipids for myelin membrane synthesis. Mouse models of plasmalogen disorders. The Pex2, Pex5, or Pex13 knockout mouse models of peroxisome biogene- sis disorder have reduced nervous system plasmalogen lev- els ( 78–81 ), but how this contributes to myelin lipid defects is difﬁ cult to establish due to the contribution of the other defects in peroxisome lipid metabolism ( Fig. 5 ). The Pex7 ( 77 ) and dihydroxyacetone phosphate acyl transferase ( 89 ) knockout mice were generated as mouse models of rhizomeluic chondrodysplasia type 1 and 2, respectively, both peroxisomal disorders that are characterized by a shortage of ether lipids and delays in myelination ( 80 ). In Pex7 knockout mice, a small reduction in CNS myelin pro- tein levels was observed, and PNS nerves showed thinning of the myelin sheath and a reduced motor nerve conduc- tion velocity ( 76 ). In the knockout mouse for Dhapat, a peroxisomal enzyme essential for plasmalogen synthesis, reduced CNS myelination was observed together with ab- normal paranodal structure and reduced corpus callosum Fig. 6. Human inherited and mouse experimental defects in conduction velocity ( 90 ). Together, these studies suggest a general lipid metabolism that cause myelin disorders. Solid line structural role of plasmalogens in myelin membrane, al- arrows depict direct link between two steps, dashed line arrows im- though ultrastructural studies remain necessary to unravel plies intermediate steps that are not shown. Dashed line circle rep- resents the citric acid cycle in mitochondria. Dark gray oval shows the precise role of plasmalogens in myelination. Further- positions of human disease genes; light gray oval shows the position more, plasmalogens are described to function as a sink of of mutated genes in an experimental mouse model. PC, pyruvate car- polyunsaturated fatty acids (PUFAs) ( 91 ) and as such pro- boxylase; PCD, pyruvate carboxylase deﬁ ciency; ASPA, asparto- posed to have a protective role against the effects of acetylase; CD, Canavan disease; NAA, N-acetylaspartic acid; FA, PUFA accumulation as seen in peroxisome disorders fatty acids. ( 92 ). Indeed, Pex7:Abcd1 knockout mice show an in- crease in VLCFA accumulation and inﬂ ammatory demy- Mouse models of general lipid disorders. Two mouse mod- elination ( 76 ). els of CD, in which ASPA is deleted, show myelin vacuoliza- tion similar to human Canavan patients ( 102, 103 ), and General lipogenesis disorders reduced brain levels for acetate, myelin lipids, and myelin Several myelin disorders are caused by defects in early proteins ( 104, 105 ). Labeling studies have shown that NAA steps in the synthesis of lipids ( Table 2 , Fig. 6 ). Pyruvate is a major source of acetate for lipid synthesis during brain carboxylase deﬁ ciency [PCD ( 93, 94 )] is caused by a muta- development and that neuronal-derived NAA supplies ace- tion in pyruvate carboxylase, an enzyme required for the tyl groups for myelin lipid synthesis ( 106, 107 ). Its quanti- synthesis of oxaloacetate of pyruvate in the tricarboxylic tative signiﬁ cance for myelin synthesis is not completely acid cycle, which is found in glial cells, predominantly as- clear because in most cell types, the enzyme ATP-citrate lyase trocytes ( 95–97 ). Several biochemical pathways rely on the provides the acetyl groups for fatty acid synthesis. Madha- tricarboxylic acid cycle, such as biosynthesis of fatty acids, varao and colleagues ( 104 ) recently suggested that the nonessential amino acids, and gluconeogenesis. Conse- lowering of acetate in ASPA knockout mice is sufﬁ cient to quently, PCD patients show CNS hypomyelination, whereas decrease myelin synthesis. However, ultrastructural analy- PNS myelin defects have not been described. Canavan dis- sis of myelin during development remains to be done in ease [CD ( 98 )] is caused by a mutation in aspartoacylase order to determine the precise consequence of ASPA deﬁ - (ASPA), an enzyme that in the rodent nervous system was ciency on myelin formation. Recently, it was shown that shown to be predominantly expressed in oligodendrocytes defective survival and differentiation of immature oligo- ( 99 ) and is involved in the deacetylation of the nervous dendrocytes may also be implicated in CD ( 108 ). Further- system speciﬁ c metabolite N-acetylaspartic acid (NAA), more, the toxic effects of NAA in myelin vacuolization should thus generating free acetate in the brain. Patients affected not be neglected ( 109 ). by CD show accumulation of neuronal NAA and reduced The role of glial lipid synthesis in myelination was re- levels of acetate in oligodendrocytes, the latter is generally cently studied by Verheijen et al. ( 110 ). It was shown that thought to limit fatty acid and membrane lipid synthesis the acute phase of myelin lipid synthesis is regulated by and to underlie the spongiform myelin degeneration, sterol regulatory element-binding protein (SREBP) cleav- while leaving neurons intact ( 100, 101 ). age activating protein (SCAP), an activator of SREBPs. 426 Journal of Lipid Research Volume 52, 2011 P0cre-SCAP mice, which carry a Schwann cell speciﬁ c de- Glycosphingolipids consist of a ceramide backbone, letion of SCAP, showed congenital hypomyelination, and formed by a long-chain fatty acyl residue linked by its am- had a loss of SREBP-mediated gene expression involved in ide bond to a long-chain sphingosine base that binds the cholesterol and fatty acids synthesis. Interestingly, SCAP functional group galactosyl or sulfatide. They pack tightly mutant Schwann cells were able to slowly synthesize mye- and have the remarkable property that their ﬂ uid/solid phase transition temperature is above body temperature, lin in an external lipid-dependent fashion, resulting in my- so that glycolipids have a solid ‘gel’ phase at body temper- elin membrane defects that were associated with abnormal ature ( 118–120 ). Accordingly, CGT knockout mice, which lipid composition. Saturated VLCFAs (C22:0 and C24:0) lack glycosphingolipids, have increased myelin membrane were found to be reduced in myelin membranes, while poly-unsaturated fatty acids (C18:2, C22:6, C24:2, C25:2 ﬂ uidity and therefore increased ion permeability, which may disrupt saltatory conduction ( 121 ). In addition to and C26:2) were increased. The reduced saturation level this, the anionic glycol group may provide an electronic of long-chain fatty acids resulted in an increase in disorder shielding on the outside of the myelin membrane and of acyl groups in the myelin lipid bilayer, which may lead thereby contribute to the electric isolation by the myelin to altered packaging of proteins in the membrane ( 111 ) membrane and thus nerve conduction velocity. Interest- and consequent ultrastructural myelin abnormalities. ingly, glycosphingolipids are solubilized by cholesterol These observations also showed that glial cells are able to ( 122 ), and both lipids are predominantly present in the take up lipids from the extracellular environment and uti- outer leaﬂ et of the myelin membrane. Asymmetric distri- lize these for myelin membrane synthesis, which is in line bution of lipids between two bilayer leaﬂ ets contributes to with the observation of Saher et al. ( 51, 52 ) on CNPcre- curving of membranes ( 122 ). This suggests a role of gly- SQS mice in which cholesterol deﬁ cient myelinating glial cosphingolipids and cholesterol in regulating ﬂ uidity and cells are able to slowly synthesize myelin. curving of myelin membranes, which could be particularly relevant for the paranodal loops structure. In line with this WHY ARE MYELINATING GLIAL CELLS is the nodal phenotype of galactolipids-lacking CGT and PARTICULARLY VULNERABLE TO LIPID CST knockout mice ( 63 ). METABOLISM DISORDERS? Plasmalogens are a sub-class of ether phospholipids, which are glycerol-derived compounds that carry an ether- The unique lipid composition of myelin critically linked carbohydrate chain on the ﬁ rst carbon of glycerol contributes to its function as opposed to ester-linked fatty acid chain in classical phos- Much of the vulnerability of myelin for lipid defects is pholipid containing a vinyl group next to the ether bond. caused by the fact that myelin membrane assembly re- The particular role of plasmalogens in membranes has not quires an extraordinary amount of lipids, especially for the been elucidated, but they are thought to play a role in lipids that are enriched in myelin: galactolipids, choles- membrane fusion processes and membrane dynamics. terol, plasmalogens, and fatty acids. As described above, They increase membrane ﬂ uidity by lowering the transi- for each of these lipid classes, human myelin disorders tion of phospholipid mixtures from a lamellar to a liquid have been described in which the pathophysiology is re- crystalline phase and stimulate the formation of nonbi- lated to lipotoxicity as a result of the accumulation of met- layer lipid structures when present in high concentration abolic precursors for myelin lipids. The vulnerability of ( 123 ). Accordingly, plasmalogens could be involved in my- myelin for lipid disorders could, however, also relate to elin membrane formation or maintenance by potentiating biochemical properties of each lipid class for functioning membrane dynamics ( 124 ). of the myelin membrane. The brain is enriched in long PUFAs like DHA (c22:6) Cholesterol is one of the most important regulators of ( 125 ). However, this enrichment is not manifested in lipid organization in the membrane. The hydroxyl group myelin, which instead contains high levels of saturated of cholesterol interacts with the polar head group of other VLCFA, and has a particularly high C18:1/C18:2 ratio (see lipids, whereas the rigid body of cholesterol is situated Fig. 2 ). Because of its high degree of saturation, phospho- along side the fatty acid tails of lipids in the membrane lipids containing these fatty acids may decrease membrane and can help to order these tails. The increased lateral ﬂ uidity and give a higher degree of fatty acid ordering in ordering of lipids that is caused by cholesterol conse- the membrane, which prevents intercalation of polar mol- quently affects the biophysical properties of the membrane ecules into the lipids. Together with the extra-long length by decreasing ﬂ uidity and reducing the permeability of of the acyl chains, this will provide a thick permeability polar molecules, like ions, for example ( 112–115 ). By con- barrier for ions and as such contribute to electric insula- trast, too much ordering is detrimental because this could tion of the axon. slow down the diffusion of membrane proteins and decrease Considering their structural role in the membrane, we the bending capacity of the membrane ( 112, 114, 116, 117 ). view that many of the lipids that are enriched in myelin Furthermore, some membrane proteins bind tightly to play a role in its axon-insulating property: the electric cholesterol as discussed below. Together, this gives choles- shielding in the outer leaﬂ et by glycolipids, the thick and terol the capacity to regulate membrane ﬂ uidity and to stabi- ordered bilayer made by the long and saturated FA, and lize and seal the membrane, all functions that seem critical the further sealing of the outer leaﬂ et by cholesterol. It for the insulating function of the myelin membrane ( 8 ). should be noted that the speciﬁ c myelin lipid composition Lipids in myelinating glial cells 427 is also likely to be related to proper packing of the myelin ing glial cells are synthesizing most of the lipids themselves, membrane. Changes in lipid composition affect lipid- but 2 ) myelinating glial cells are still able to synthesize my- protein interactions causing an altered packing of proteins elin when endogenous lipid synthesis has been shut down, in the membrane ( 111 ). For instance, proteins and lipids albeit at a very low level. This indicates that these cells have may work synergistically to provide proper structure to my- the capacity to take up lipids from the extracellular envi- elin membranes ( 126 ). In line with this, interference with ronment. Accordingly, transcription analysis in rodents endogenous Schwann cell lipid metabolism in P0cre-SCAP showed that lipoprotein receptors are expressed by oligo- mutant mice increases the unsaturation level of fatty acids dendrocytes ( 127 ) and that expression of the low density in myelin and is accompanied by ultrastructural defects in lipoprotein receptor (LDLR) gene in the PNS is elevated myelin membrane packing ( 110 ). with myelination ( 24 ) although the LDLR gene was found Together, these data suggest that lipids may control in- not to be required for PNS remyelination ( 128 ). Which li- sulation of the axon and proper structure of the myelin poprotein receptors are involved in the uptake of lipids membrane ( Fig. 7 ). Both of these aspects are clearly af- and exactly where on the glial cell they can be found to fected in many lipid metabolic disorders, but it remains to support membrane growth ( Fig. 1 ) is currently unclear. be determined whether small functional defects on nerve The exact contribution of extracellular lipid supply for mye- function in certain cases are caused by more subtle changes lin membrane synthesis under normal conditions remains in myelin lipid composition that affect axonal insulation. to be determined, but is likely to be small ( Fig. 7 ). Defects It is furthermore tempting to speculate that myelinating in glial lipid synthesis will therefore consequently lead to glial cells may control nerve conduction velocity by regula- defective myelin membrane synthesis. tion of its myelin lipid content. Myelin lipids regulate the transport and localization of Timely myelination requires extraordinarily high levels of myelin proteins lipid synthesis together with uptake of extracellular lipids In addition to the above mentioned synchronized ex- Much of the vulnerability of myelin for lipid defects is pression of transcripts encoding structural myelin proteins caused by the fact that myelin membrane assembly re- and enzymes involved in myelin lipid biosynthesis, recent quires an extraordinary amount of lipids. The observations data suggest that glial lipid levels regulate myelin protein on CNPcre-SQS ko mice ( 51, 52 ) and P0cre-SCAP ko mice trafﬁ cking and thus also myelin assembly ( 52 )( 129 ). In oli- ( 110 ) have led to two important conclusions: 1 ) myelinat- godendrocytes, proteolipid protein (PLP) associates with lipid rafts before exiting the Golgi apparatus, suggesting that myelin lipid and proteins assemble in the Golgi com- plex. Indeed, the cholesterol- and galactosylceramide-rich lipid rafts were shown to be required for proper sorting of PLP to myelin ( 129 ). In line with this, certain mutations in PLP perturb interactions with cholesterol and lipid rafts, which may contribute to dysmyelination as found in spastic paraplegia ( 130 ). Similarly, disrupted Schwann cell cho- lesterol biosynthesis led to partial mislocalization of my- elin protein P0, resulting in noncompaction of the myelin membrane and hypomyelination ( 52 ). Additional cell cul- ture experiments demonstrated that this defect could be restored by cholesterol supplementation, and showed the critical role of the myelin protein P0 cholesterol recogni- tion/interaction amino acid consensus motif for its cor- rect trafﬁ cking from endoplasmic reticulum to the myelin compartment. Furthermore, elevation of extracellular cho- lesterol or lipoprotein levels was demonstrated to increase Fig. 7. Schematic diagram of the various roles of lipids in myeli- myelination by Schwann cells in vitro ( 52, 110 ). Together, nating glial cells. Gray ovals show the processes that are affected by these data suggest that lipids may control myelin protein lipid metabolism and involved in myelinated ﬁ ber function. High lipid levels, which are required for synthesis of a full myelin mem- trafﬁ cking and thereby assembly and compaction of the my- brane, are ensured by both the endogenous synthesis of lipids as by elin membrane ( Fig. 7 ). This lipid-mediated control mech- the uptake of lipids from the extracellular environment. Lipids inﬂ u- anism of myelin protein sorting is likely to be deregulated ence myelinating glial cell differentiation and trafﬁ cking of myelin in lipid metabolic disorders, but whether and how it is used proteins to the myelin membrane. The unique lipid composition by myelinating glial cells to control myelin membrane syn- of the myelin membrane is required for proper myelin membrane thesis under healthy conditions remains to be determined. wrapping (compaction) and electrostatic isolation of the axon from extracellular environment, thereby promoting saltatory conduc- tion and conduction velocity. Question marks show processes with Lipids regulate differentiation of myelinating glial cells a potential effect on myelin ﬁ ber function: the inﬂ uence of lipid- The regulatory role of lipids in differentiation of myeli- speciﬁ c diets on myelin lipid dependent processes, and the possi- nating glial cells was demonstrated in oligodendrocytes ble role of myelin lipids in metabolic support of the axon. See text and in Schwann cells. Both the cell culture experiments for further explanation. 428 Journal of Lipid Research Volume 52, 2011 and the data from CGT and CST knockout animals re- somal biogenesis factor 5 (Pex5) led to generation of animals vealed an increased number of terminally differentiated with disrupted peroxisomal function in oligodendrocytes oligodendrocytes (OLs) in the absence of galactosphingo- and Schwann cells [see above ( 82 )]. Interestingly, al- lipids ( 131, 132 ). Based on these results, two putative reg- though the affected animals were able to assemble normal ulatory mechanisms involving galactosphingolipids were myelin, they developed progressive axonal loss followed by suggested: either they could play a direct role in cell adhe- demyelination. Based on these data it was suggested that sion necessary for correct timing of OL differentiation or the observed axonal loss could be, at least partially, a con- they can have an indirect role affecting signaling proteins sequence of disrupted glial -oxidation normally executed present in plasma membrane thus disturbing OL differen- in peroxisomes, leading to a diminished capacity to meta- tiation ( 132 ). In the PNS, phosphatidic acid (PA) was shown bolically support the underlying axons ( 73 ). A similar hy- to affect Schwann cell differentiation ( 133 ). Demyelina- pothesis suggesting the role of lipids in “energy-on-demand” tion in Lpin1 mutant mice was suggested to be mediated supply for active axons was proposed based on expression by increased levels of PA. Subsequent cell culture experi- analysis of genes encoding proteins involved in lipid me- ments demonstrated that PA induces Schwann cell dedif- tabolism in the adult peripheral nerve ( 24, 136 ). Although ferentiation via activation of the MEK-Erk pathway revealing further clariﬁ cation of the involvement of lipids in axonal its role in glial cell fate determination ( 133 ) ( Fig. 7 ). support is still needed, it was shown that the expression of sterol response binding protein 1c (Srebp1c), which is the key transcriptional regulator of storage lipid metabolism, MYELIN LIPIDS AS DETERMINANTS FOR is affected in Schwann cells of a rodent model of diabetic NERVE FIBER FUNCTION peripheral neuropathy ( 137 ). Together, therefore, these data suggest that local glial lipid metabolism plays a crucial The process of myelination represents an interesting para- role not only in myelination but also in glial support of digm to study the metabolism and transport of lipids. Myeli- underlying axons. nation by rodent glial cells is, both in vivo and in vitro, ﬁ nalized within a one- to two-week interval. Because during Implications for therapeutic interventions that target this period a myelinating glial cell needs to expand its mem- lipid metabolism brane up to 6,500 times, one can consider these cells as “lipid A working strategy against lipotoxicity would be to use producing factories”. For instance, transcriptional analysis of drugs that inhibit lipid accumulation. For instance, phar- myelinating glial cells clearly revealed that the most coregu- lated group of genes expressed during the period of myelina- macological targeting of the cholesterol pathway, by statin- induced inhibition of HMG-CoA reductase, is used in CTX tion are lipid biosynthesis-related transcripts ( 23, 24 ). to inhibit the accumulation of cholestan ( 138 ). Impor- Lipids as markers for myelin membrane integrity tantly, statins are widely used for the treatment of hyper- and function cholesterolemia, and some statins, e.g., Lovastatin and Simvastatin, are able to cross the blood-brain barrier ( 139 ). Much of the structure and function of myelin is depen- Remarkably, statins can ameliorate remyelination in an dent on its lipid content. Lipids may therefore be used as markers for myelin membrane integrity and associated animal model of multiple sclerosis (MS) ( 140–143 ), possi- nerve ﬁ ber function. The C18:1/C18:2 ratio is a well- bly via augmenting survival and differentiation of oligo- dendrocyte progenitors, and therefore have been tested in described marker for the progression of myelination of the MS trials ( 144, 145 ). However, statins induce the forma- PNS ( 7 ) and the CNS ( 134 ). In addition, a high level of PUFA in PNS myelin suggests a strong contribution of ex- tion of abnormal myelin-like membrane sheets in primary ogenous lipids in building of the myelin membrane ( 110 ). oligodendrocytes in vitro, due to impairment of cholesterol- dependent myelin protein transport ( 146 ), which indi- High cholesterol levels are required for the formation of cates a risk of the use of statins for myelin membrane compact myelin (with high P0), with low cholesterol levels resulting in increased amounts of noncompact myelin integrity. In addition, statins are reported to increase the [with myelin-associated glycoprotein (MAG)] ( 52 ). This risk of developing peripheral neuropathy ( 147 ), although there is some controversy concerning the exact amplitude suggests that the cholesterol content of myelin is indica- of this risk, which furthermore appeared to be reversible tive for its compaction status. Dedifferentiation of myeli- nating Schwann cells in the Lpin1 mutant appeared to be and will need further study ( 148, 149 ). The major contri- mediated by high PA levels ( 133 ). This suggests that high bution of endogenous lipid metabolism by myelinating glial cells implies that inhibition of glial lipid metabolism, PA levels are indicative for an active anti-myelination pro- especially during the active period of myelination, may un- gram, although it remains to be determined whether PA is also instrumental in regulating (de)differentiation in derlie the development of demyelinating neuropathy, and other paradigms, e.g., during development or injury. as such warrants for care in the use of lipid-lowering drugs especially during late pregnancies and early postnatal Myelin lipids provide direct support to axonal function; development. a hypothesis Extracellular supply of lipids may be a working strategy A possible role of myelinating glial cells in trophic sup- for treatment of lipid deﬁ cit in myelinating glial cells. Ob- servations of mice with lipid-deﬁ cient glial cells show that port of underlying axons was recently suggested ( 135 ). Previous data demonstrated that inactivation of peroxi- myelinating glial cells are able to take up lipids from the Lipids in myelinating glial cells 429 extracellular environment ( 51, 52, 150 ). This is, however, of local hypolipidemia induced by pathological conditions complicated by the blood-nerve barrier and the blood- like genetic lipid disorders, myelinating glial cells may be brain barrier that shield, respectively, the PNS and CNS able to obtain lipids derived from the circulation or from from lipids in the circulation ( 151, 152 ). Therefore, the other nervous system compartments, albeit at a very low nervous system is classically viewed as being largely autono- level. mous in lipid metabolism. Despite this dogma, dietary ap- As summarized in this review, our knowledge about the proaches to rescue lipid deﬁ cits are used in several lipid role of lipids in myelin biology increased substantially disorders to treat myelin defects. In SLOS, cholesterol from the analysis of inherited myelin disorders with defec- supplementation leads to good biochemical and physical tive lipid metabolism and their related mouse models. These new data point to a far more complex role of lipids changes in nonneuronal tissues ( 153 ). Changes in neu- ronal tissues are limited, also because of the inability to in myelinating glial cells than solely being building blocks reverse developmental defects, although striking behav- for the myelin membrane ( Fig. 7 ). Lipid metabolism is im- ioral improvements involving both CNS and PNS function- portant for glial cell development and function; lipids af- fect glial cell differentiation, are involved in myelin protein ing were found ( 44, 45, 154 ). In a rodent model for CD, glyceryltriacetate supplementation was recently reported trafﬁ cking and myelin compaction, and may potentially to improve motor performance and myelin lipid content contribute to mature myelinating glial cell support of en- ( 155 ). In Zellweger patients, alkyl-glycerol supplementa- wrapped axons. Importantly, these new data also show that despite the requirement of timely local glial lipid synthesis tion to rescue plasmalogen deﬁ ciency has been performed for normal myelination, myelinating glial cells are able to with only little success ( 156 ), which may be related to the other peroxisomal defects that are not related to plasmalo- take up lipids from the surrounding environment. To- gen deﬁ ciency in these patients. Interestingly, in Pex7 gether, these insights may contribute to the development of therapeutic approaches aiming at the preservation of knockout mice, a model for rhizomeluic chondrodysplasia myelin under pathological conditions that affect lipid me- type 1, alkyl-glycerol supplementation improves PNS plas- malogen levels and nerve function (P. Brites, personal tabolism. communication). The above-described changes may not involve lipid up- The authors thank Dr. J. F. Brouwers for advice and fatty acid take by the nervous system, but instead be indirect conse- analysis. quences of lipid supplementation. For instance, lipid metabolism in Schwann cells is under the inﬂ uence of the nutritional status of mice through a mechanism probably REFERENCES involving insulin signaling ( 137 ). Recent studies have also shed light on novel mechanisms of cholesterol exchange 1 . Barres , B. A. 2008 . The mystery and magic of glia: a perspective on between the CNS and circulating lipoproteins under cer- their roles in health and disease. Neuron . 60 : 430 – 440 . 2 . Franz , D. N. , and A. Iggo . 1968 . Conduction failure in myelinated tain physiological or pathological conditions. Saito et al. and non-myelinated axons at low temperatures. J. Physiol. 199 : ( 157 ) recently showed that deletion of SQS in neural 319 – 345 . stem cells led to neuronal cell death, however, not of pro- 3 . Waxman , S. G. 1980 . Determinants of conduction velocity in mye- linated nerve ﬁ bers. Muscle Nerve . 3 : 141 – 150 . genitor cells at the subventricular zone that protected 4 . Hartline , D. K. , and D. R. Colman . 2007 . Rapid conduction and themselves against cholesterol deprivation by promoting the evolution of giant axons and myelinated ﬁ bers. Curr. Biol. 17 : angiogenesis and consequently raising their lipoprotein R29 – R35 . 5 . Norton , W. T. , and S. E. Poduslo . 1973 . Myelination in rat brain: cholesterol supply from the circulation. Furthermore, it method of myelin isolation. J. Neurochem. 21 : 749 – 757 . was reported that speciﬁ c loss of brain ABCA1, which is 6 . Norton , W. T. , and S. E. Poduslo . 1973 . Myelination in rat brain: required for efﬂ ux of cellular cholesterol, not only pro- changes in myelin composition during brain maturation. J. Neurochem. 21 : 759 – 773 . duced the expected reduction in brain cholesterol, but 7 . Garbay , B. , A. M. Heape , F. Sargueil , and C. Cassagne . 2000 . remarkably, also led to an apparently compensatory in- Myelin synthesis in the peripheral nervous system. Prog. Neurobiol. crease in the speciﬁ c uptake of esteriﬁ ed cholesterol from 61 : 267 – 304 . plasma HDL particles into the CNS ( 158 ). The observed 8 . Saher , G. , and M. Simons . 2010 . Cholesterol and myelin biogene- sis. Subcell. Biochem. 51 : 489 – 508 . increase in HDL receptor SR-B1 in brain capillaries of 9 . Norton , W. T. , and W. Cammer . 1984 . Isolation and characteriza- these mice, together with the recent ﬁ nding that lipopro- tion of myelin. In Myelin. P. Morell, editor. Plenum, New York. tein receptors in brain capillary cells can be used for tar- 147–180. 10 . Stoffel , W. , and A. Bosio . 1997 . Myelin glycolipids and their func- geting of compounds across the blood-brain barrier ( 159 ), tions. Curr. Opin. Neurobiol. 7 : 654 – 661 . indicate that the shielding of the CNS from circulating lip- 11 . Eckhardt , M. 2008 . The role and metabolism of sulfatide in the ids may not be as strict as thought for a long time. This is nervous system. Mol. Neurobiol. 37 : 93 – 103 . 12 . Nagan , N. , and R. A. Zoeller . 2001 . Plasmalogens: biosynthesis certainly the case for circulating unsaturated fatty acids. and functions. Prog. Lipid Res. 40 : 199 – 229 . For instance, PNS myelin in P0cre-SCAP mutant mice con- 13 . Balakrishnan , S. , H. Goodwin , and J. N. Cumings . 1961 . The dis- tains more polyunsaturated fatty acids, and have higher tribution of phosphorus-containing lipid compounds in the hu- man brain. J. Neurochem. 8 : 276 – 284 . C18:2 levels, which is consistent with an increased uptake 14 . Morell , P. , and R.H. Quarles. 1999 . Myelin formation, structure of essential fatty acids from external sources ( 160 ). Consis- and biochemistry. In Basic Neurochemistry. J. S. George, B. W. tent with this, circulating fatty acids are incorporated into Agranoff, R. W. Albers, S. F. Fisher, and M. D. Uhler, editors. Lippincott-Raven, Philedelphia. adult myelin ( 161, 162 ). Taken together, in the situation 430 Journal of Lipid Research Volume 52, 2011 15 . Sowell , E. R. , B. S. Peterson , P. M. Thompson , S. E. Welcome , A. MRS ﬁ ndings in Smith-Lemli-Opitz syndrome. Neuroradiology . 46 : L. Henkenius , and A. W. Toga . 2003 . Mapping cortical change 3 – 14 . across the human life span. Nat. Neurosci. 6 : 309 – 315 . 37 . Kelley , R. I. , and R. C. Hennekam . 2000 . The Smith-Lemli-Opitz 16 . Yakovlev , P. I. , and A. R. Lecours . 1967 . The myelogenetic cycles syndrome. J. Med. Genet. 37 : 321 – 335 . of regional maturation of the brain. In Regional Development of 38 . Curry , C. J. , J. C. Carey , J. S. Holland , D. Chopra , R. Fineman , the Brain in Early Life. A. Minkowski, editor. Blackwell Scientiﬁ c, M. Golabi , S. Sherman , R. A. Pagon , J. Allanson , S. Shulman , et al . Oxford. 3–70. 1987 . Smith-Lemli-Opitz syndrome-type II: multiple congenital 17 . Muse , E. D. , H. Jurevics , A. D. Toews , G. K. Matsushima , and P. anomalies with male pseudohermaphroditism and frequent early Morell . 2001 . Parameters related to lipid metabolism as markers lethality. Am. J. Med. Genet. 26 : 45 – 57 . of myelination in mouse brain. J. Neurochem. 76 : 77 – 86 . 39 . Ryan , A. K. , K. Bartlett , P. Clayton , S. Eaton , L. Mills , D. Donnai , 18 . Baron , W. , and D. Hoekstra . 2009 . On the biogenesis of myelin R. M. Winter , and J. Burn . 1998 . Smith-Lemli-Opitz syndrome: membranes: sorting, trafﬁ cking and cell polarity. FEBS Lett. 584 : a variable clinical and biochemical phenotype. J. Med. Genet. 35 : 1760 – 1770 . 558 – 565 . 19 . Webster , H. D. 1971 . The geometry of peripheral myelin sheaths 40 . Berry , R. , H. Wilson , J. Robinson , C. Sandlin , W. Tyson , J. during their formation and growth in rat sciatic nerves. J. Cell Biol. Campbell , R. Porreco , and D. Manchester . 1989 . Apparent Smith- 48 : 348 – 367 . Lemli-Opitz syndrome and Miller-Dieker syndrome in a family 20 . Heape , A. , H. Juguelin , M. Fabre , F. Boiron , B. Garbay , M. with segregating translocation t(7;17)(q34;p13.1). Am. J. Med. Fournier , J. Bonnet , and C. Cassagne . 1986 . Correlation between Genet. 34 : 358 – 365 . the morphology and the lipid and protein compositions in the 41 . Cherstvoy , E. D. , G. I. Lazjuk , T. I. Ostrovskaya , I. A. Shved , G. I. peripheral nervous system of individual 8-day-old normal and Kravtzova , I. W. Lurie , and A. I. Gerasimovich . 1984 . The Smith- trembler mice. Brain Res. 390 : 173 – 180 . Lemli-Opitz syndrome. A detailed pathological study as a clue to a 21 . Heape , A. , H. Juguelin , M. Fabre , F. Boiron , and C. Cassagne . etiological heterogeneity. Virchows Arch. 404 : 413 – 425 . 1986 . A quantitative developmental study of the peripheral nerve 42 . Ness , G. C. , D. Lopez , O. Borrego , and E. Gilbert-Barness . 1997 . lipid composition during myelinogenesis in normal and trembler Increased expression of low-density lipoprotein receptors in a mice. Brain Res. 390 : 181 – 189 . Smith-Lemli-Opitz infant with elevated bilirubin levels. Am. J. 22 . Heape , A. , F. Boiron , and C. Cassagne . 1987 . A developmental Med. Genet. 68 : 294 – 299 . study of fatty acyl group contents in the peripheral nervous system 43 . Fierro , M. , A. J. Martinez , J. W. Harbison , and S. H. Hay . 1977 . of normal and trembler mice. Neurochem. Pathol. 7 : 157 – 167 . Smith-Lemli-Opitz syndrome: neuropathological and ophthalmo- 23 . Nagarajan , R. , N. Le , H. Mahoney , T. Araki , and J. Milbrandt . logical observations. Dev. Med. Child Neurol. 19 : 57 – 62 . 2002 . Deciphering peripheral nerve myelination by using 44 . Elias , E. R. , M. B. Irons , A. D. Hurley , G. S. Tint , and G. Salen . Schwann cell expression proﬁ ling. Proc. Natl. Acad. Sci. USA . 1997 . Clinical effects of cholesterol supplementation in six pa- 99 : 8998 – 9003 . tients with the Smith-Lemli-Opitz syndrome (SLOS). Am. J. Med. 24 . Verheijen , M. H. , R. Chrast , P. Burrola , and G. Lemke . 2003 . Local Genet. 68 : 305 – 310 . regulation of fat metabolism in peripheral nerves. Genes Dev. 17 : 45 . Irons , M. , E. R. Elias , D. Abuelo , M. J. Bull , C. L. Greene , V. P. 2450 – 2464 . Johnson , L. Keppen , C. Schanen , G. S. Tint , and G. Salen . 1997 . 25 . Ando , S. , Y. Tanaka , Y. Toyoda , and K. Kon . 2003 . Turnover of Treatment of Smith-Lemli-Opitz syndrome: results of a multicen- myelin lipids in aging brain. Neurochem. Res. 28 : 5 – 13 . ter trial. Am. J. Med. Genet. 68 : 311 – 314 . 26 . Dyck , P. J. , and P. K. Thomas . 2005 . Lysosomal and peroxi- 46 . Porter , F. D. 2000 . RSH/Smith-Lemli-Opitz syndrome: a multi- somal disorders. In Peripheral Neuropathy. Elsevier Saunders, ple congenital anomaly/mental retardation syndrome due to an Philadelphia, PA. 1845–1882. inborn error of cholesterol biosynthesis. Mol. Genet. Metab. 71 : 27 . Wanders , R. J. , S. Ferdinandusse , P. Brites , and S. Kemp . 2010 . 163 – 174 . Peroxisomes, lipid metabolism and lipotoxicity. Biochim. Biophys. 47 . Starck , L. , I. Bjorkhem , E. M. Ritzen , B. Y. Nilsson , and U. von Acta . 1801 : 272 – 280 . Dobeln . 1999 . Beneﬁ cial effects of dietary supplementation in a 28 . Horster , F. , R. Surtees , and G. F. Hoffmann . 2005 . Disorders of disorder with defective synthesis of cholesterol. A case report of intermediary metabolism: toxic leukoencephalopathies. J. Inherit. a girl with Smith-Lemli-Opitz syndrome, polyneuropathy and pre- Metab. Dis. 28 : 345 – 356 . cocious puberty. Acta Paediatr. 88 : 729 – 733 . 29 . Verrips , A. , L. H. Hoefsloot , G. C. Steenbergen , J. P. Theelen , 48 . Fitzky , B. U. , F. F. Moebius , H. Asaoka , H. Waage-Baudet , L. R. A. Wevers , F. J. Gabreels , B. G. van Engelen , and L. P. van Xu , G. Xu , N. Maeda , K. Kluckman , S. Hiller , H. Yu , et al . 2001 . den Heuvel . 2000 . Clinical and molecular genetic characteristics 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reduc- of patients with cerebrotendinous xanthomatosis. Brain . 123 : tase suppresses sterol biosynthesis in a mouse model of Smith- 908 – 919 . Lemli-Opitz/RSH syndrome. J. Clin. Invest. 108 : 905 – 915 . 30 . Gallus , G. N. , M. T. Dotti , and A. Federico . 2006 . Clinical and 49 . Wassif , C. A. , P. Zhu , L. Kratz , P. A. Krakowiak , K. P. Battaile , F. F. molecular diagnosis of cerebrotendinous xanthomatosis with Weight , A. Grinberg , R. D. Steiner , N. A. Nwokoro , R. I. Kelley , a review of the mutations in the CYP27A1 gene. Neurol. Sci. 27 : et al . 2001 . Biochemical, phenotypic and neurophysiological 143 – 149 . characterization of a genetic mouse model of RSH/Smith–Lemli– 31 . Pietrini , V. , N. Rizzuto , C. Vergani , F. Zen , and F. Ferro Milone . Opitz syndrome. Hum. Mol. Genet. 10 : 555 – 564 . 1985 . Neuropathy in Tangier disease: A clinicopathologic study 50 . Correa-Cerro , L. S. , C. A. Wassif , L. Kratz , G. F. Miller , J. P. and a review of the literature. Acta Neurol. Scand. 72 : 495 – 505 . Munasinghe , A. Grinberg , S. J. Fliesler , and F. D. Porter . 2006 . 32 . Pollock , M. , H. Nukada , R. W. Frith , J. P. Simcock , and S. Allpress . Development and characterization of a hypomorphic Smith- 1983 . Peripheral neuropathy in Tangier disease. Brain . 106 : Lemli-Opitz syndrome mouse model and efﬁ cacy of simvastatin 911 – 928 . therapy. Hum. Mol. Genet. 15 : 839 – 851 . 33 . Neklason , D. W. , K. M. Andrews , R. I. Kelley , and J. E. Metherall . 51 . Saher , G. , B. Brugger , C. Lappe-Siefke , W. Mobius , R. Tozawa , 1999 . Biochemical variants of Smith-Lemli-Opitz syndrome. Am. J. M. C. Wehr , F. Wieland , S. Ishibashi , and K. A. Nave . 2005 . High Med. Genet. 85 : 517 – 523 . cholesterol level is essential for myelin membrane growth. Nat. 34 . Witsch-Baumgartner , M. , B. U. Fitzky , M. Ogorelkova , H. G. Kraft , Neurosci. 8 : 468 – 475 . F. F. Moebius , H. Glossmann , U. Seedorf , G. Gillessen-Kaesbach , 52 . Saher , G. , S. Quintes , W. Mobius , M. C. Wehr , E. M. Kramer- G. F. Hoffmann , P. Clayton , et al . 2000 . Mutational spectrum in Albers , B. Brugger , and K. A. Nave . 2009 . Cholesterol regulates the Delta7-sterol reductase gene and genotype-phenotype cor- the endoplasmic reticulum exit of the major membrane protein relation in 84 patients with Smith-Lemli-Opitz syndrome. Am. J. P0 required for peripheral myelin compaction. J. Neurosci. 29 : Hum. Genet. 66 : 402 – 412 . 6094 – 6104 . 35 . Ciara , E. , M. J. Nowaczyk , M. Witsch-Baumgartner , E. Malunowicz , 53 . von Figura , K. , V. Gieselmann , and J. Jaeken . 2001 . Metachromatic E. Popowska , A. Jezela-Stanek , M. Piotrowicz , J. S. Waye , G. leukodystrophy. In The Metabolic And Molecular Basis of Utermann , and M. Krajewska-Walasek . 2004 . DHCR7 mutations Inherited Disease. C. R. Scriver, A. L. Beaudet, D. Valle, W. S. Sly, and genotype-phenotype correlation in 37 Polish patients with editors. McGraw Hill, New York. 3695–3724. Smith-Lemli-Opitz syndrome. Clin. Genet. 66 : 517 – 524 . 54 . Landrieu , P. , and G. Said . 1984 . Peripheral neuropathy in type A 36 . Caruso , P. A. , T. Y. Poussaint , A. A. Tzika , D. Zurakowski , L. G. Niemann-Pick disease. A morphological study. Acta Neuropathol. Astrakas , E. R. Elias , C. Bay , and M. B. Irons . 2004 . MRI and 1H 63 : 66 – 71 . Lipids in myelinating glial cells 431 55 . Suzuki , K. 2003 . Globoid cell leukodystrophy (Krabbe’s disease): 74 . Van Veldhoven , P. P. 2010 . Biochemistry and genetics of inher- update. J. Child Neurol. 18 : 595 – 603 . ited disorders of peroxisomal fatty acid metabolism. J. Lipid Res. 56 . Schuchman , E. H. , and R. J. Desnick . 2001 . Niemann-Pick dis- 51 : 2863 – 2895 . ease types A and B: acid sphingomyelinase deﬁ ciencies. In The 75 . Imgrund , S. , D. Hartmann , H. Farwanah , M. Eckhardt , R. Metabolic and Molecular Basis of Inherited Disease. C. R. Scriver, Sandhoff , J. Degen , V. Gieselmann , K. Sandhoff , and K. Willecke . A. L. Beaudet, W. S. Sly, D. Valle, B. Childs, K. W. Kinzler, and B. 2009 . Adult ceramide synthase 2 (CERS2)-deﬁ cient mice exhibit Vogelstein, editors. McGraw-Hill, New York. 3589–3610. myelin sheath defects, cerebellar degeneration, and hepatocarci- 57 . Edvardson , S. , H. Hama , A. Shaag , J. M. Gomori , I. Berger , D. nomas. J. Biol. Chem. 284 : 33549 – 33560 . Soffer , S. H. Korman , I. Taustein , A. Saada , and O. Elpeleg . 2008 . 76 . Brites , P. , P. A. Mooyer , L. El Mrabet , H. R. Waterham , and R. J. Mutations in the fatty acid 2-hydroxylase gene are associated with Wanders . 2009 . Plasmalogens participate in very-long-chain fatty leukodystrophy with spastic paraparesis and dystonia. Am. J. Hum. acid-induced pathology. Brain . 132 : 482 – 492 . Genet. 83 : 643 – 648 . 77 . Brites , P. , A. M. Motley , P. Gressens , P. A. Mooyer , I. Ploegaert , 58 . Dick , K. J. , M. Eckhardt , C. Paisan-Ruiz , A. A. Alshehhi , C. V. Everts , P. Evrard , P. Carmeliet , M. Dewerchin , L. Schoonjans , Proukakis , N. A. Sibtain , H. Maier , R. Shariﬁ , M. A. Patton , W. et al . 2003 . Impaired neuronal migration and endochondral os- Bashir , et al . 2010 . Mutation of FA2H underlies a complicated siﬁ cation in Pex7 knockout mice: a model for rhizomelic chon- form of hereditary spastic paraplegia (SPG35). Hum. Mutat. 31 : drodysplasia punctata. Hum. Mol. Genet. 12 : 2255 – 2267 . E1251 – E1260 . 78 . Maxwell , M. , J. Bjorkman , T. Nguyen , P. Sharp , J. Finnie , C. 59 . Alderson , N. L. , B. M. Rembiesa , M. D. Walla , A. Bielawska , J. Paterson , I. Tonks , B. C. Paton , G. F. Kay , and D. I. Crane . 2003 . Bielawski , and H. Hama . 2004 . The human FA2H gene encodes a Pex13 inactivation in the mouse disrupts peroxisome biogenesis fatty acid 2-hydroxylase. J. Biol. Chem. 279 : 48562 – 48568 . and leads to a Zellweger syndrome phenotype. Mol. Cell. Biol. 23 : 60 . Zoller , I. , M. Meixner , D. Hartmann , H. Bussow , R. Meyer , V. 5947 – 5957 . Gieselmann , and M. Eckhardt . 2008 . Absence of 2-hydroxylated 79 . Faust , P. L. , and M. E. Hatten . 1997 . Targeted deletion of the sphingolipids is compatible with normal neural development PEX2 peroxisome assembly gene in mice provides a model for but causes late-onset axon and myelin sheath degeneration. J. Zellweger syndrome, a human neuronal migration disorder. J. Cell Neurosci. 28 : 9741 – 9754 . Biol. 139 : 1293 – 1305 . 61 . Enquist , I. B. , C. Lo Bianco , A. Ooka , E. Nilsson , J. E. Mansson , M. 80 . Baes , M. , and P. Aubourg . 2009 . Peroxisomes, myelination, and Ehinger , J. Richter , R. O. Brady , D. Kirik , and S. Karlsson . 2007 . axonal integrity in the CNS. Neuroscientist . 15 : 367 – 379 . Murine models of acute neuronopathic Gaucher disease. Proc. 81 . Baes , M. , P. Gressens , E. Baumgart , P. Carmeliet , M. Casteels , Natl. Acad. Sci. USA . 104 : 17483 – 17488 . M. Fransen , P. Evrard , D. Fahimi , P. E. Declercq , D. Collen , 62 . Hailemariam , T. K. , C. Huan , J. Liu , Z. Li , C. Roman , M. et al . 1997 . A mouse model for Zellweger syndrome. Nat. Genet. Kalbfeisch , H. H. Bui , D. A. Peake , M. S. Kuo , G. Cao , et al . 2008 . 17 : 49 – 57 . Sphingomyelin synthase 2 deﬁ ciency attenuates NFkappaB activa- 82 . Kassmann , C. M. , C. Lappe-Siefke , M. Baes , B. Brugger , tion. Arterioscler. Thromb. Vasc. Biol. 28 : 1519 – 1526 . A. Mildner , H. B. Werner , O. Natt , T. Michaelis , M. Prinz , 63 . Marcus , J. , S. Honigbaum , S. Shroff , K. Honke , J. Rosenbluth , and J. Frahm , et al . 2007 . Axonal loss and neuroinﬂ ammation J. L. Dupree . 2006 . Sulfatide is essential for the maintenance of caused by peroxisome-deﬁ cient oligodendrocytes. Nat. Genet. CNS myelin and axon structure. Glia . 53 : 372 – 381 . 39 : 969 – 976 . 64 . Hoshi , T. , A. Suzuki , S. Hayashi , K. Tohyama , A. Hayashi , Y. 83 . Powers , J. M. , Y. Liu , A. B. Moser , and H. W. Moser . 1992 . The Yamaguchi , K. Takeuchi , and H. Baba . 2007 . Nodal protrusions, inﬂ ammatory myelinopathy of adreno-leukodystrophy: cells, ef- increased Schmidt-Lanterman incisures, and paranodal disorga- fector molecules, and pathogenetic implications. J. Neuropathol. nization are characteristic features of sulfatide-deﬁ cient periph- Exp. Neurol. 51 : 630 – 643 . eral nerves. Glia . 55 : 584 – 594 . 84 . Ito , M. , B. M. Blumberg , D. J. Mock , A. D. Goodman , A. B. Moser , 65 . Coetzee , T. , N. Fujita , J. Dupree , R. Shi , A. Blight , K. Suzuki , and H. W. Moser , K. D. Smith , and J. M. Powers . 2001 . Potential B. Popko . 1996 . Myelination in the absence of galactocerebroside environmental and host participants in the early white matter and sulfatide: normal structure with abnormal function and re- lesion of adreno-leukodystrophy: morphologic evidence for gional instability. Cell . 86 : 209 – 219 . CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1- 66 . Saadat , L. , J. L. Dupree , J. Kilkus , X. Han , M. Traka , R. L. Proia , mediated lipid antigen presentation. J. Neuropathol. Exp. Neurol. G. Dawson , and B. Popko . 2010 . Absence of oligodendroglial 60 : 1004 – 1019 . glucosylceramide synthesis does not result in CNS myelin abnor- 85 . elMasry , M. N. , and R. R. Rich . 1989 . Prostaglandin E2 selectively malities or alter the dysmyelinating phenotype of CGT-deﬁ cient increases interferon gamma receptor expression on human CD8+ mice. Glia . 58 : 391 – 398 . lymphocytes. J. Clin. Invest. 83 : 1436 – 1440 . 67 . Rizzo , W. B. , G. Carney , and Z. Lin . 1999 . The molecular basis 86 . Jozefowski , S. , R. Biedron , M. Bobek , and J. Marcinkiewicz . 2005 . of Sjogren-Larsson syndrome: mutation analysis of the fatty alde- Leukotrienes modulate cytokine release from dendritic cells. hyde dehydrogenase gene. Am. J. Hum. Genet. 65 : 1547 – 1560 . Immunology . 116 : 418 – 428 . 68 . Willemsen , M. A. , M. Van Der Graaf , M. S. Van Der Knaap , A. 87 . Schepers , L. , M. Casteels , J. Vamecq , G. Parmentier , P. P. Van Heerschap , P. H. Van Domburg , F. J. Gabreels , and J. J. Rotteveel . Veldhoven , and G. P. Mannaerts . 1988 . Beta-oxidation of the car- 2004 . MR imaging and proton MR spectroscopic studies in boxyl side chain of prostaglandin E2 in rat liver peroxisomes and Sjogren-Larsson syndrome: characterization of the leukoenceph- mitochondria. J. Biol. Chem. 263 : 2724 – 2731 . alopathy. AJNR Am. J. Neuroradiol. 25 : 649 – 657 . 88 . Ferdinandusse , S. , T. Meissner , R. J. Wanders , and E. Mayatepek . 69 . van Domburg , P. H. , M. A. Willemsen , J. J. Rotteveel , J. G. de Jong , 2002 . Identiﬁ cation of the peroxisomal beta-oxidation enzymes H. O. Thijssen , A. Heerschap , J. R. Cruysberg , R. J. Wanders , F. involved in the degradation of leukotrienes. Biochem. Biophys. Res. J. Gabreels , and P. M. Steijlen . 1999 . Sjogren-Larsson syndrome: Commun. 293 : 269 – 273 . clinical and MRI/MRS ﬁ ndings in FALDH-deﬁ cient patients. 89 . Rodemer , C. , T. P. Thai , B. Brugger , T. Kaercher , H. Werner , K. Neurology . 52 : 1345 – 1352 . A. Nave , F. Wieland , K. Gorgas , and W. W. Just . 2003 . Inactivation 70 . Wierzbicki , A. S. , M. D. Lloyd , C. J. Schoﬁ eld , M. D. Feher , of ether lipid biosynthesis causes male infertility, defects in eye de- and F. B. Gibberd . 2002 . Refsum’s disease: a peroxisomal dis- velopment and optic nerve hypoplasia in mice. Hum. Mol. Genet. order affecting phytanic acid alpha-oxidation. J. Neurochem. 80 : 12 : 1881 – 1895 . 727 – 735 . 90 . Teigler , A. , D. Komljenovic , A. Draguhn , K. Gorgas , and W. W. 71 . Steinberg , S. J. , G. Dodt , G. V. Raymond , N. E. Braverman , A. B. Just . 2009 . Defects in myelination, paranode organization and Moser , and H. W. Moser . 2006 . Peroxisome biogenesis disorders. Purkinje cell innervation in the ether lipid-deﬁ cient mouse cere- Biochim. Biophys. Acta . 1763 : 1733 – 1748 . bellum. Hum. Mol. Genet. 18 : 1897 – 1908 . 72 . Mayatepek , E. , M. Baumann , T. Meissner , F. Hanefeld , and G. C. 91 . Tamby , J. P. , P. Reinaud , and G. Charpigny . 1996 . Preferential es- Korenke . 2003 . Role of leukotrienes as indicators of the inﬂ am- teriﬁ cation of arachidonic acid into ethanolamine phospholipids matory demyelinating reaction in x–linked cerebral adrenoleu- in epithelial cells from ovine endometrium. J. Reprod. Fertil. 107 : kodystrophy. J. Neurol. 250 : 1259 – 1260 . 23 – 30 . 73 . Kassmann , C. M. , and K. A. Nave . 2008 . Oligodendroglial impact 92 . Brites , P. , H. R. Waterham , and R. J. Wanders . 2004 . Functions on axonal function and survival - a hypothesis. Curr. Opin. Neurol. and biosynthesis of plasmalogens in health and disease. Biochim. 21 : 235 – 241 . Biophys. Acta . 1636 : 219 – 231 . 432 Journal of Lipid Research Volume 52, 2011 93 . Marin-Valencia , I. , C. R. Roe , and J. M. Pascual . 2010 . Pyruvate 113 . Sankaram , M. B. , and T. E. Thompson . 1990 . Modulation of phos- carboxylase deﬁ ciency: mechanisms, mimics and anaplerosis. Mol. pholipid acyl chain order by cholesterol. A solid-state 2H nuclear Genet. Metab. 101 : 9 – 17 . magnetic resonance study. Biochemistry . 29 : 10676 – 10684 . 94 . Schiff , M. , V. Levrat , C. Acquaviva , C. Vianey-Saban , M. O. 114 . Huang , J. , and G. W. Feigenson . 1999 . A microscopic interaction Rolland , and N. Guffon . 2006 . A case of pyruvate carboxylase de- model of maximum solubility of cholesterol in lipid bilayers. ﬁ ciency with atypical clinical and neuroradiological presentation. Biophys. J. 76 : 2142 – 2157 . Mol. Genet. Metab. 87 : 175 – 177 . 115 . Kakorin , S. , U. Brinkmann , and E. Neumann . 2005 . Cholesterol 95 . Cesar , M. , and B. Hamprecht . 1995 . Immunocytochemical exam- reduces membrane electroporation and electric deformation of ination of neural rat and mouse primary cultures using monoclo- small bilayer vesicles. Biophys. Chem. 117 : 155 – 171 . nal antibodies raised against pyruvate carboxylase. J. Neurochem. 116 . Pan , J. , S. Tristram-Nagle , and J. F. Nagle . 2009 . Effect of cho- 64 : 2312 – 2318 . lesterol on structural and mechanical properties of membranes 96 . Shank , R. P. , G. S. Bennett , S. O. Freytag , and G. L. Campbell . depends on lipid chain saturation. Phys. Rev. E Stat. Nonlin. Soft 1985 . Pyruvate carboxylase: an astrocyte-speciﬁ c enzyme impli- Matter Phys. 80 : 021931 . cated in the replenishment of amino acid neurotransmitter pools. 117 . Hofsass , C. , E. Lindahl , and O. Edholm . 2003 . Molecular dynamics Brain Res. 329 : 364 – 367 . simulations of phospholipid bilayers with cholesterol. Biophys. J. 97 . Murin , R. , M. Cesar , B. S. Kowtharapu , S. Verleysdonk , and B. 84 : 2192 – 2206 . Hamprecht . 2009 . Expression of pyruvate carboxylase in cultured 118 . Wang , T. Y. , and J. R. Silvius . 2003 . Sphingolipid partitioning into oligodendroglial, microglial and ependymal cells. Neurochem. Res. ordered domains in cholesterol-free and cholesterol-containing 34 : 480 – 489 . lipid bilayers. Biophys. J. 84 : 367 – 378 . 98 . Namboodiri , A. M. , A. Peethambaran , R. Mathew , P. A. Sambhu , 119 . Kulkarni , K. , D. S. Snyder , and T. J. McIntosh . 1999 . Adhesion J. Hershﬁ eld , J. R. Moffett , and C. N. Madhavarao . 2006 . Canavan between cerebroside bilayers. Biochemistry . 38 : 15264 – 15271 . disease and the role of N-acetylaspartate in myelin synthesis. Mol. 120 . Ruocco , M. J. , D. Atkinson , D. M. Small , R. P. Skarjune , E. Oldﬁ eld , Cell. Endocrinol. 252 : 216 – 223 . and G. G. Shipley . 1981 . X-ray diffraction and calorimetric study 99 . Madhavarao , C. N. , J. R. Moffett , R. A. Moore , R. E. Viola , M. A. of anhydrous and hydrated N-palmitoylgalactosylsphingosine (ce- Namboodiri , and D. M. Jacobowitz . 2004 . Immunohistochemical rebroside). Biochemistry . 20 : 5957 – 5966 . localization of aspartoacylase in the rat central nervous system. 121 . Bosio , A. , E. Binczek , W. F. Haupt , and W. Stoffel . 1998 . Composi- J. Comp. Neurol. 472 : 318 – 329 . tion and biophysical properties of myelin lipid deﬁ ne the neuro- 100 . Adachi , M. , L. Schneck , J. Cara , and B. W. Volk . 1973 . Spongy logical defects in galactocerebroside- and sulfatide-deﬁ cient mice. degeneration of the central nervous system (van Bogaert and J. Neurochem. 70 : 308 – 315 . Bertrand type; Canavan’s disease). A review. Hum. Pathol. 4 : 122 . van Meer , G. , D. R. Voelker , and G. W. Feigenson . 2008 . Membrane 331 – 347 . lipids: where they are and how they behave. Nat. Rev. Mol. Cell Biol. 101 . Gascon , G. G. , P. T. Ozand , A. Mahdi , A. Jamil , A. Haider , J. 9 : 112 – 124 . Brismar , and M. al-Nasser . 1990 . Infantile CNS spongy degener- 123 . Glaser , P. E. , and R. W. Gross . 1994 . Plasmenylethanolamine facil- ation–14 cases: clinical update. Neurology . 40 : 1876 – 1882 . itates rapid membrane fusion: a stopped-ﬂ ow kinetic investigation 102 . Matalon , R. M. , and K. Michals-Matalon . 2000 . Spongy degener- correlating the propensity of a major plasma membrane constit- ation of the brain, Canavan disease: biochemical and molecular uent to adopt an HII phase with its ability to promote membrane ﬁ ndings. Front. Biosci. 5 : D307 – D311 . fusion. Biochemistry . 33 : 5805 – 5812 . 103 . Traka , M. , R. L. Wollmann , S. R. Cerda , J. Dugas , B. A. Barres , 124 . Glaser , P. E. , and R. W. Gross . 1995 . Rapid plasmenylethano l- and B. Popko . 2008 . Nur7 is a nonsense mutation in the mouse amine-selective fusion of membrane bilayers catalyzed by an aspartoacylase gene that causes spongy degeneration of the CNS. isoform of glyceraldehyde-3-phosphate dehydrogenase: discrimi- J. Neurosci. 28 : 11537 – 11549 . nation between glycolytic and fusogenic roles of individual iso- 104 . Madhavarao , C. N. , P. Arun , J. R. Moffett , S. Szucs , S. Surendran , forms. Biochemistry . 34 : 12193 – 12203 . R. Matalon , J. Garbern , D. Hristova , A. Johnson , W. Jiang , et al . 125 . Sastry , P. S. 1985 . Lipids of nervous tissue: composition and me- 2005 . Defective N-acetylaspartate catabolism reduces brain ace- tabolism. Prog. Lipid Res. 24 : 69 – 176 . tate levels and myelin lipid synthesis in Canavan’s disease. Proc. 126 . Hu , Y. , I. Doudevski , D. Wood , M. Moscarello , C. Husted , C. Natl. Acad. Sci. USA . 102 : 5221 – 5226 . Genain , J. A. Zasadzinski , and J. Israelachvili . 2004 . Synergistic in- 105 . Ledeen , R. W. , J. Wang , G. Wu , Z. H. Lu , G. Chakraborty , M. teractions of lipids and myelin basic protein. Proc. Natl. Acad. Sci. Meyenhofer , S. K. Tyring , and R. Matalon . 2006 . Physiological USA . 101 : 13466 – 13471 . role of N-acetylaspartate: contribution to myelinogenesis. Adv. 127 . Zhao , S. , X. Hu , J. Park , Y. Zhu , Q. Zhu , H. Li , C. Luo , R. Han , Exp. Med. Biol. 576 : 131–143; discussion 361–133. N. Cooper , and M. Qiu . 2007 . Selective expression of LDLR and 106 . Namboodiri , A. M. , J. R. Moffett , P. Arun , R. Mathew , S. VLDLR in myelinating oligodendrocytes. Dev. Dyn. 236 : 2708 – 2712 . Namboodiri , A. Potti , J. Hershﬁ eld , B. Kirmani , D. M. Jacobowitz , 128 . Goodrum , J. F. , K. A. Fowler , J. D. Hostettler , and A. D. Toews . and C. N. Madhavarao . 2006 . Defective myelin lipid synthesis as a 2000 . Peripheral nerve regeneration and cholesterol reutiliza- pathogenic mechanism of Canavan disease. Adv. Exp. Med. Biol. tion are normal in the low-density lipoprotein receptor knockout 576 : 145–163; discussion 361–143. mouse. J. Neurosci. Res. 59 : 581 – 586 . 107 . Chakraborty , G. , P. Mekala , D. Yahya , G. Wu , and R. W. Ledeen . 129 . Simons , M. , E. M. Kramer , C. Thiele , W. Stoffel , and J. Trotter . 2001 . Intraneuronal N-acetylaspartate supplies acetyl groups for 2000 . Assembly of myelin by association of proteolipid protein myelin lipid synthesis: evidence for myelin-associated aspartoacy- with cholesterol- and galactosylceramide-rich membrane do- lase. J. Neurochem. 78 : 736 – 745 . mains. J. Cell Biol. 151 : 143 – 154 . 108 . Kumar , S. , J. C. Biancotti , R. Matalon , and J. de Vellis . 2009 . Lack 130 . Kramer-Albers , E. M. , K. Gehrig-Burger , C. Thiele , J. Trotter , and of aspartoacylase activity disrupts survival and differentiation of K. A. Nave . 2006 . Perturbed interactions of mutant proteolipid neural progenitors and oligodendrocytes in a mouse model of protein/DM20 with cholesterol and lipid rafts in oligodendroglia: Canavan disease. J. Neurosci. Res. 87 : 3415 – 3427 . implications for dysmyelination in spastic paraplegia. J. Neurosci. 109 . Baslow , M. H. , and D. N. Guilfoyle . 2009 . Are astrocytes the miss- 26 : 11743 – 11752 . ing link between lack of brain aspartoacylase activity and the 131 . Bansal , R. , S. Winkler , and S. Bheddah . 1999 . Negative regula- spongiform leukodystrophy in Canavan disease? Neurochem. Res. tion of oligodendrocyte differentiation by galactosphingolipids. 34 : 1523 – 1534 . J. Neurosci. 19 : 7913 – 7924 . 110 . Verheijen , M. H. , N. Camargo , V. Verdier , K. Nadra , A. S. de 132 . Hirahara , Y. , R. Bansal , K. Honke , K. Ikenaka , and Y. Wada . Preux Charles , J. J. Medard , A. Luoma , M. Crowther , H. Inouye , 2004 . Sulfatide is a negative regulator of oligodendrocyte H. Shimano , et al . 2009 . SCAP is required for timely and proper differentiation: development in sulfatide-null mice. Glia . 45 : myelin membrane synthesis. Proc. Natl. Acad. Sci. USA . 106 : 269 – 277 . 21383 – 21388 . 133 . Nadra , K. , A. S. de Preux Charles , J. J. Medard , W. T. Hendriks , 111 . Lee , A. G. 2003 . Lipid-protein interactions in biological mem- G. S. Han , S. Gres , G. M. Carman , J. S. Saulnier-Blache , M. H. branes: a structural perspective. Biochim. Biophys. Acta . 1612 : 1 – 40 . Verheijen , and R. Chrast . 2008 . Phosphatidic acid mediates demy- 112 . Simons , K. , and W. L. Vaz . 2004 . Model systems, lipid rafts, elination in Lpin1 mutant mice. Genes Dev. 22 : 1647 – 1661 . and cell membranes. Annu. Rev. Biophys. Biomol. Struct. 33 : 134 . Huether , G. , M. Klapproth , and V. Neuhoff . 1986 . Fatty acid co- 269 – 295 . mposition of myelin lipids from developing rat forebrain and Lipids in myelinating glial cells 433 spinal cord: inﬂ uence of experimental hyperphenylalaninaemia. 156 . Das , A. K. , R. D. Holmes , G. N. Wilson , and A. K. Hajra . 1992 . Neurochem. Res. 11 : 1303 – 1311 . Dietary ether lipid incorporation into tissue plasmalogens of hu- 135 . Nave , K. A. 2010 . Myelination and the trophic support of long mans and rodents. Lipids . 27 : 401 – 405 . axons. Natl. Rev. 11 : 275 – 283 . 157 . Saito , K. , V. Dubreuil , Y. Arai , M. Wilsch-Brauninger , D. Schwudke , 136 . Chrast , R. , M. H. Verheijen , and G. Lemke . 2004 . Complement G. Saher , T. Miyata , G. Breier , C. Thiele , A. Shevchenko , et al . factors in adult peripheral nerve: a potential role in energy me- 2009 . Ablation of cholesterol biosynthesis in neural stem cells in- tabolism. Neurochem. Int. 45 : 353 – 359 . creases their VEGF expression and angiogenesis but causes neu- 137 . de Preux , A. S. , K. Goosen , W. Zhang , A. A. Sima , H. Shimano , ron apoptosis. Proc. Natl. Acad. Sci. USA . 106 : 8350 – 8355 . D. M. Ouwens , M. Diamant , J. L. Hillebrands , J. Rozing , G. 158 . Karasinska , J. M. , F. Rinninger , D. Lutjohann , P. Ruddle , S. Lemke , et al . 2007 . SREBP-1c expression in Schwann cells is Franciosi , J. K. Kruit , R. R. Singaraja , V. Hirsch-Reinshagen , J. Fan , affected by diabetes and nutritional status. Mol. Cell. Neurosci. L. R. Brunham , et al . 2009 . Speciﬁ c loss of brain ABCA1 increases 35 : 525 – 534 . brain cholesterol uptake and inﬂ uences neuronal structure and 138 . Verrips , A. , R. A. Wevers , B. G. Van Engelen , A. Keyser , B. G. function. J. Neurosci. 29 : 3579 – 3589 . Wolthers , F. Barkhof , A. Stalenhoef , R. De Graaf , F. Janssen- 159 . Spencer , B. J. , and I. M. Verma . 2007 . Targeted delivery of pro- Zijlstra , A. Van Spreeken , et al . 1999 . Effect of simvastatin in addi- teins across the blood-brain barrier. Proc. Natl. Acad. Sci. USA . 104 : tion to chenodeoxycholic acid in patients with cerebrotendinous 7594 – 7599 . xanthomatosis. Metabolism . 48 : 233 – 238 . 160 . Garbay , B. , F. Boiron-Sargueil , M. Shy , T. Chbihi , H. Jiang , J. 139 . Saheki , A. , T. Terasaki , I. Tamai , and A. Tsuji . 1994 . In vivo and in Kamholz , and C. Cassagne . 1998 . Regulation of oleoyl-CoA syn- vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl thesis in the peripheral nervous system: demonstration of a link coenzyme A (HMG-CoA) reductase inhibitors. Pharm. Res. 11 : with myelin synthesis. J. Neurochem. 71 : 1719 – 1726 . 305 – 311 . 161 . Yao , J. K. , R. T. Holman , M. F. Lubozynski , and P. J. Dyck . 1980 . 140 . Paintlia , A. S. , M. K. Paintlia , M. Khan , T. Vollmer , A. K. Singh , Changes in fatty acid composition of peripheral nerve mye- and I. Singh . 2005 . HMG-CoA reductase inhibitor augments sur- lin in essential fatty acid deﬁ ciency. Arch. Biochem. Biophys. 204 : vival and differentiation of oligodendrocyte progenitors in animal 175 – 180 . model of multiple sclerosis . Faseb. J. 19 : 1407 – 1421 . 162 . Bourre , J. M. , A. Youyou , G. Durand , and G. Pascal . 1987 . Slow 141 . Paintlia , A. S. , M. K. Paintlia , A. K. Singh , and I. Singh . 2008 . recovery of the fatty acid composition of sciatic nerve in rats fed a Inhibition of rho family functions by lovastatin promotes myelin diet initially low in n-3 fatty acids. Lipids . 22 : 535 – 538 . repair in ameliorating experimental autoimmune encephalomy- 163 . Retra , K. , O. B. Bleijerveld , R. A. van Gestel , A. G. Tielens , J. J. elitis. Mol. Pharmacol. 73 : 1381 – 1393 . van Hellemond , and J. F. Brouwers . 2008 . A simple and universal 142 . Stanislaus , R. , A. G. Gilg , A. K. Singh , and I. Singh . 2002 . Immu- method for the separation and identiﬁ cation of phospholipid mo- nomodulation of experimental autoimmune encephalomyelitis lecular species. Rapid Commun. Mass Spectrom. 22 : 1853 – 1862 . in the Lewis rats by Lovastatin. Neurosci. Lett. 333 : 167 – 170 . 164 . Dod , B. J. , and G. M. Gray . 1968 . The lipid composition of rat-liver 143 . Youssef , S. , O. Stuve , J. C. Patarroyo , P. J. Ruiz , J. L. Radosevich , E. plasma membranes. Biochim. Biophys. Acta . 150 : 397 – 404 . M. Hur , M. Bravo , D. J. Mitchell , R. A. Sobel , L. Steinman , and S. 165 . Ray , T. K. , V. P. Skipski , M. Barclay , E. Essner , and F. M. Archibald . S. Zamvil . 2002 . The HMG-CoA reductase inhibitor, atorvastatin, 1969 . Lipid composition of rat liver plasma membranes. J. Biol. promotes a Th2 bias and reverses paralysis in central nervous sys- Chem. 244 : 5528 – 5536 . tem autoimmune disease. Nature. 420 : 78 – 84 . 166 . Lorincz , M. T. , S. Rainier , D. Thomas , and J. K. Fink . 2005 . Cere- 144 . Sena , A. , R. Pedrosa , and M. Graca Morais . 2003 . Therapeutic po- brotendinous xanthomatosis: possible higher prevalence than tential of lovastatin in multiple sclerosis. J. Neurol. 250 : 754 – 755 . previously recognized. Arch. Neurol. 62 : 1459 – 1463 . 145 . Vollmer , T. , L. Key , V. Durkalski , W. Tyor , J. Corboy , S. Markovic- 167 . Brunham , L. R. , R. R. Singaraja , and M. R. Hayden . 2006 . Vari- Plese , J. Preiningerova , M. Rizzo , and I. Singh . 2004 . Oral simvas- ations on a gene: rare and common variants in ABCA1 and their tatin treatment in relapsing-remitting multiple sclerosis . Lancet. impact on HDL cholesterol levels and atherosclerosis. Annu. Rev. 363 : 1607 – 1608 . Nutr. 26 : 105 – 129 . 146 . Maier , O. , J. De Jonge , A. Nomden , D. Hoekstra , and W. Baron . 168 . Heim , P. , M. Claussen , B. Hoffmann , E. Conzelmann , J. Gartner , 2009 . Lovastatin induces the formation of abnormal myelin- K. Harzer , D. H. Hunneman , W. Kohler , G. Kurlemann , and A. like membrane sheets in primary oligodendrocytes. Glia . 57 : Kohlschutter . 1997 . Leukodystrophy incidence in Germany. Am. 402 – 413 . J. Med. Genet. 71 : 475 – 478 . 147 . Gaist , D. , U. Jeppesen , M. Andersen , L. A. Garcia Rodriguez , J. 169 . Gustavson , K. H. , and B. Hagberg . 1971 . The incidence and ge- Hallas , and S. H. Sindrup . 2002 . Statins and risk of polyneuropa- netics of metachromatic leucodystrophy in northern Sweden. Acta thy: a case-control study. Neurology . 58 : 1333 – 1337 . Paediatr. Scand. 60 : 585 – 590 . 148 . Law , M. , and A. R. Rudnicka . 2006 . Statin safety: a systematic re- 170 . Schuchman , E. H. 2007 . The pathogenesis and treatment of view. Am. J. Cardiol. 97 : 52C – 60C . acid sphingomyelinase-deﬁ cient Niemann-Pick disease. J. Inherit. 149 . Brown , W. V. 2008 . Safety of statins. Curr. Opin. Lipidol. 19 : Metab. Dis. 30 : 654 – 663 . 558 – 562 . 171 . Jagell , S. , K. H. Gustavson , and G. Holmgren . 1981 . Sjogren- 150 . Verhave , P. S. , R. A. Vanwersch , H. P. van Helden , A. B. Smit , and Larsson syndrome in Sweden. A clinical, genetic and epidemio- I. H. Philippens . 2009 . Two new test methods to quantify motor logical study. Clin. Genet. 19 : 233 – 256 . deﬁ cits in a marmoset model for Parkinson’s disease. Behav. Brain 172 . Lazarow , P. B. , and H. W. Moser . 1989 . Disorders of peroxisome Res. 200 : 214 – 219 . biogenesis. In The Metabolic Basis of Inherited Disease. C. R. 151 . Jurevics , H. A. , and P. Morell . 1994 . Sources of cholesterol for Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, editors. McGraw- kidney and nerve during development. J. Lipid Res. 35 : 112 – 120 . Hill, New York. 1479–1509. 152 . Morell , P. , and H. Jurevics . 1996 . Origin of cholesterol in myelin. 173 . Berger , J. , and J. Gartner . 2006 . X-linked adrenoleukodystrophy: Neurochem. Res. 21 : 463 – 470 . clinical, biochemical and pathogenetic aspects. Biochim. Biophys. 153 . Kelley , R. I. 2000 . Inborn errors of cholesterol biosynthesis. Adv. Acta . 1763 : 1721 – 1732 . Pediatr. 47 : 1 – 53 . 174 . Feigenbaum , A. , R. Moore , J. Clarke , S. Hewson , D. Chitayat , P. N. 154 . Ullrich , K. , H. G. Koch , D. Meschede , U. Flotmann , and U. Ray , and T. L. Stockley . 2004 . Canavan disease: carrier-frequency Seedorf . 1996 . Smith-Lemli-Opitz syndrome: treatment with cho- determination in the Ashkenazi Jewish population and develop- lesterol and bile acids. Neuropediatrics . 27 : 111 – 112 . ment of a novel molecular diagnostic assay. Am. J. Med. Genet. A. 155 . Arun , P. , C. N. Madhavarao , J. R. Moffett , K. Hamilton , N. E. 124A : 142 – 147 . Grunberg , P. S. Ariyannur , W. A. Gahl , Y. Anikster , S. Mog , W. C. 175 . Brun , N. , Y. Robitaille , A. Grignon , B. H. Robinson , G. A. Mitchell , Hallows , et al . 2010 . Metabolic acetate therapy improves pheno- and M. Lambert . 1999 . Pyruvate carboxylase deﬁ ciency: prenatal type in the tremor rat model of Canavan disease. J. Inherit. Metab. onset of ischemia-like brain lesions in two sibs with the acute neo- Dis. 33 : 195 – 210 . natal form. Am. J. Med. Genet. 84 : 94 – 101 . 434 Journal of Lipid Research Volume 52, 2011

Journal

Journal of Lipid Research – American Society for Biochemistry and Molecular Biology

Published: Mar 1, 2011

References

The mystery and magic of glia: a perspective on their roles in health and disease

B.A. Barres
Conduction failure in myelinated and non-myelinated axons at low temperatures

A. Iggo
Determinants of conduction velocity in myelinated nerve fibers

S.G. Waxman
Rapid conduction and the evolution of giant axons and myelinated fibers

D.R. Colman
Myelination in rat brain: method of myelin isolation

S.E. Poduslo
Myelination in rat brain: changes in myelin composition during brain maturation

S.E. Poduslo
Myelin synthesis in the peripheral nervous system

C. Cassagne
Cholesterol and myelin biogenesis

M. Simons
Myelin glycolipids and their functions

A. Bosio
The role and metabolism of sulfatide in the nervous system

M. Eckhardt
Plasmalogens: biosynthesis and functions

R.A. Zoeller
The distribution of phosphorus-containing lipid compounds in the human brain

J.N. Cumings
Myelin formation, structure and biochemistry

R.H. Quarles
Mapping cortical change across the human life span

A.W. Toga
The myelogenetic cycles of regional maturation of the brain

A.R. Lecours
Parameters related to lipid metabolism as markers of myelination in mouse brain

P. Morell
On the biogenesis of myelin membranes: sorting, trafficking and cell polarity

D. Hoekstra
The geometry of peripheral myelin sheaths during their formation and growth in rat sciatic nerves

H.D. Webster
Correlation between the morphology and the lipid and protein compositions in the peripheral nervous system of individual 8-day-old normal and trembler mice

C. Cassagne
A quantitative developmental study of the peripheral nerve lipid composition during myelinogenesis in normal and trembler mice

C. Cassagne
A developmental study of fatty acyl group contents in the peripheral nervous system of normal and trembler mice

C. Cassagne
Deciphering peripheral nerve myelination by using Schwann cell expression profiling

J. Milbrandt
Local regulation of fat metabolism in peripheral nerves

G. Lemke
Turnover of myelin lipids in aging brain

K. Kon
Lysosomal and peroxisomal disorders. In, Peripheral Neuropathy

P.K. Thomas
Peroxisomes, lipid metabolism and lipotoxicity

S. Kemp
Disorders of intermediary metabolism: toxic leukoencephalopathies

G.F. Hoffmann
Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis

L.P. van den Heuvel
Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene

A. Federico
Neuropathy in Tangier disease: A clinicopathologic study and a review of the literature

F. Ferro Milone
Peripheral neuropathy in Tangier disease

S. Allpress
Biochemical variants of Smith-Lemli-Opitz syndrome

J.E. Metherall
Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome

P. Clayton
DHCR7 mutations and genotype-phenotype correlation in 37 Polish patients with Smith-Lemli-Opitz syndrome

M. Krajewska-Walasek
MRI and 1H MRS findings in Smith-Lemli-Opitz syndrome

M.B. Irons
The Smith-Lemli-Opitz syndrome

R.C. Hennekam
Smith-Lemli-Opitz syndrome-type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality

S. Shulman
Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype

J. Burn
Apparent Smith-Lemli-Opitz syndrome and Miller-Dieker syndrome in a family with segregating translocation t(7

D. Manchester
The Smith-Lemli-Opitz syndrome. A detailed pathological study as a clue to a etiological heterogeneity

A.I. Gerasimovich
Increased expression of low-density lipoprotein receptors in a Smith-Lemli-Opitz infant with elevated bilirubin levels

E. Gilbert-Barness
Smith-Lemli-Opitz syndrome: neuropathological and ophthalmological observations

S.H. Hay
Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS)

G. Salen
Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial

G. Salen
RSH/Smith-Lemli-Opitz syndrome: a multiple congenital anomaly/mental retardation syndrome due to an inborn error of cholesterol biosynthesis

F.D. Porter
Beneficial effects of dietary supplementation in a disorder with defective synthesis of cholesterol. A case report of a girl with Smith-Lemli-Opitz syndrome, polyneuropathy and precocious puberty

U. von Dobeln
7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome

H. Yu
Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith–Lemli–Opitz syndrome

R.I. Kelley
Development and characterization of a hypomorphic Smith-Lemli-Opitz syndrome mouse model and efficacy of simvastatin therapy

F.D. Porter
High cholesterol level is essential for myelin membrane growth

K.A. Nave
Cholesterol regulates the endoplasmic reticulum exit of the major membrane protein P0 required for peripheral myelin compaction

K.A. Nave
Metachromatic leukodystrophy

J. Jaeken
Peripheral neuropathy in type A Niemann-Pick disease. A morphological study

G. Said
Globoid cell leukodystrophy (Krabbe's disease): update

K. Suzuki
Niemann-Pick disease types A and B: acid sphingomyelinase deficiencies

R.J. Desnick
Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia

O. Elpeleg
Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35)

W. Bashir
The human FA2H gene encodes a fatty acid 2-hydroxylase

H. Hama
Absence of 2-hydroxylated sphingolipids is compatible with normal neural development but causes late-onset axon and myelin sheath degeneration

M. Eckhardt
Murine models of acute neuronopathic Gaucher disease

S. Karlsson
Sphingomyelin synthase 2 deficiency attenuates NFkappaB activation

G. Cao
Sulfatide is essential for the maintenance of CNS myelin and axon structure

J.L. Dupree
Nodal protrusions, increased Schmidt-Lanterman incisures, and paranodal disorganization are characteristic features of sulfatide-deficient peripheral nerves

H. Baba
Myelination in the absence of galactocerebroside and sulfatide: normal structure with abnormal function and regional instability

B. Popko
Absence of oligodendroglial glucosylceramide synthesis does not result in CNS myelin abnormalities or alter the dysmyelinating phenotype of CGT-deficient mice

B. Popko
The molecular basis of Sjogren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene

Z. Lin
MR imaging and proton MR spectroscopic studies in Sjogren-Larsson syndrome: characterization of the leukoencephalopathy

J.J. Rotteveel
Sjogren-Larsson syndrome: clinical and MRI/MRS findings in FALDH-deficient patients

P.M. Steijlen
Refsum's disease: a peroxisomal disorder affecting phytanic acid alpha-oxidation

F.B. Gibberd
Peroxisome biogenesis disorders

H.W. Moser
Role of leukotrienes as indicators of the inflammatory demyelinating reaction in x–linked cerebral adrenoleukodystrophy

G.C. Korenke
Oligodendroglial impact on axonal function and survival - a hypothesis

K.A. Nave
Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism

P.P. Van Veldhoven
Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas

K. Willecke
Plasmalogens participate in very-long-chain fatty acid-induced pathology

R.J. Wanders
Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata

L. Schoonjans
Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype

D.I. Crane
Targeted deletion of the PEX2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder

M.E. Hatten
Peroxisomes, myelination, and axonal integrity in the CNS

P. Aubourg
A mouse model for Zellweger syndrome

D. Collen
Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes

J. Frahm
The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications

H.W. Moser
Potential environmental and host participants in the early white matter lesion of adreno-leukodystrophy: morphologic evidence for CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1-mediated lipid antigen presentation

J.M. Powers
Prostaglandin E2 selectively increases interferon gamma receptor expression on human CD8+ lymphocytes

R.R. Rich
Leukotrienes modulate cytokine release from dendritic cells

J. Marcinkiewicz
Beta-oxidation of the carboxyl side chain of prostaglandin E2 in rat liver peroxisomes and mitochondria

G.P. Mannaerts
Identification of the peroxisomal beta-oxidation enzymes involved in the degradation of leukotrienes

E. Mayatepek
Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice

W.W. Just
Defects in myelination, paranode organization and Purkinje cell innervation in the ether lipid-deficient mouse cerebellum

W.W. Just
Preferential esterification of arachidonic acid into ethanolamine phospholipids in epithelial cells from ovine endometrium

G. Charpigny
Functions and biosynthesis of plasmalogens in health and disease

R.J. Wanders
Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis

J.M. Pascual
A case of pyruvate carboxylase deficiency with atypical clinical and neuroradiological presentation

N. Guffon
Immunocytochemical examination of neural rat and mouse primary cultures using monoclonal antibodies raised against pyruvate carboxylase

B. Hamprecht
Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools

G.L. Campbell
Expression of pyruvate carboxylase in cultured oligodendroglial, microglial and ependymal cells

B. Hamprecht
Canavan disease and the role of N-acetylaspartate in myelin synthesis

C.N. Madhavarao
Immunohistochemical localization of aspartoacylase in the rat central nervous system

D.M. Jacobowitz
Spongy degeneration of the central nervous system (van Bogaert and Bertrand type

B.W. Volk
Infantile CNS spongy degeneration–14 cases: clinical update

M. al-Nasser
Spongy degeneration of the brain, Canavan disease: biochemical and molecular findings

K. Michals-Matalon
Nur7 is a nonsense mutation in the mouse aspartoacylase gene that causes spongy degeneration of the CNS

B. Popko
Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease

W. Jiang
Physiological role of N-acetylaspartate: contribution to myelinogenesis

R. Matalon
Defective myelin lipid synthesis as a pathogenic mechanism of Canavan disease

C.N. Madhavarao
Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase

R.W. Ledeen
Lack of aspartoacylase activity disrupts survival and differentiation of neural progenitors and oligodendrocytes in a mouse model of Canavan disease

J. de Vellis
Are astrocytes the missing link between lack of brain aspartoacylase activity and the spongiform leukodystrophy in Canavan disease?

D.N. Guilfoyle
SCAP is required for timely and proper myelin membrane synthesis

H. Shimano
Lipid-protein interactions in biological membranes: a structural perspective

A.G. Lee
Model systems, lipid rafts, and cell membranes

W.L. Vaz
Modulation of phospholipid acyl chain order by cholesterol. A solid-state 2H nuclear magnetic resonance study

T.E. Thompson
A microscopic interaction model of maximum solubility of cholesterol in lipid bilayers

G.W. Feigenson
Cholesterol reduces membrane electroporation and electric deformation of small bilayer vesicles

E. Neumann
Effect of cholesterol on structural and mechanical properties of membranes depends on lipid chain saturation

J.F. Nagle
Molecular dynamics simulations of phospholipid bilayers with cholesterol

O. Edholm
Sphingolipid partitioning into ordered domains in cholesterol-free and cholesterol-containing lipid bilayers

J.R. Silvius
Adhesion between cerebroside bilayers

T.J. McIntosh
X-ray diffraction and calorimetric study of anhydrous and hydrated N-palmitoylgalactosylsphingosine (cerebroside)

G.G. Shipley
Composition and biophysical properties of myelin lipid define the neurological defects in galactocerebroside- and sulfatide-deficient mice

W. Stoffel
Membrane lipids: where they are and how they behave

G.W. Feigenson
Plasmenylethanolamine facilitates rapid membrane fusion: a stopped-flow kinetic investigation correlating the propensity of a major plasma membrane constituent to adopt an HII phase with its ability to promote membrane fusion

R.W. Gross
Rapid plasmenylethanolamine-selective fusion of membrane bilayers catalyzed by an isoform of glyceraldehyde-3-phosphate dehydrogenase: discrimination between glycolytic and fusogenic roles of individual isoforms

R.W. Gross
Lipids of nervous tissue: composition and metabolism

P.S. Sastry
Synergistic interactions of lipids and myelin basic protein

J. Israelachvili
Selective expression of LDLR and VLDLR in myelinating oligodendrocytes

M. Qiu
Peripheral nerve regeneration and cholesterol reutilization are normal in the low-density lipoprotein receptor knockout mouse

A.D. Toews
Assembly of myelin by association of proteolipid protein with cholesterol- and galactosylceramide-rich membrane domains

J. Trotter
Perturbed interactions of mutant proteolipid protein/DM20 with cholesterol and lipid rafts in oligodendroglia: implications for dysmyelination in spastic paraplegia

K.A. Nave
Negative regulation of oligodendrocyte differentiation by galactosphingolipids

S. Bheddah
Sulfatide is a negative regulator of oligodendrocyte differentiation: development in sulfatide-null mice

Y. Wada
Phosphatidic acid mediates demyelination in Lpin1 mutant mice

R. Chrast
Fatty acid composition of myelin lipids from developing rat forebrain and spinal cord: influence of experimental hyperphenylalaninaemia

V. Neuhoff
Myelination and the trophic support of long axons

K.A. Nave
Complement factors in adult peripheral nerve: a potential role in energy metabolism

G. Lemke
SREBP-1c expression in Schwann cells is affected by diabetes and nutritional status

G. Lemke
Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis

A. Van Spreeken
In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors

A. Tsuji
HMG-CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis

I. Singh
Inhibition of rho family functions by lovastatin promotes myelin repair in ameliorating experimental autoimmune encephalomyelitis

I. Singh
Immunomodulation of experimental autoimmune encephalomyelitis in the Lewis rats by Lovastatin

I. Singh
The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease

S.S. Zamvil
Therapeutic potential of lovastatin in multiple sclerosis

M. Graca Morais
Oral simvastatin treatment in relapsing-remitting multiple sclerosis

I. Singh
Lovastatin induces the formation of abnormal myelin-like membrane sheets in primary oligodendrocytes

W. Baron
Statins and risk of polyneuropathy: a case-control study

S.H. Sindrup
Statin safety: a systematic review

A.R. Rudnicka
Safety of statins

W.V. Brown
Two new test methods to quantify motor deficits in a marmoset model for Parkinson's disease

I.H. Philippens
Sources of cholesterol for kidney and nerve during development

P. Morell
Origin of cholesterol in myelin

H. Jurevics
Inborn errors of cholesterol biosynthesis

R.I. Kelley
Smith-Lemli-Opitz syndrome: treatment with cholesterol and bile acids

U. Seedorf
Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease

W.C. Hallows
Dietary ether lipid incorporation into tissue plasmalogens of humans and rodents

A.K. Hajra
Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis

A. Shevchenko
Specific loss of brain ABCA1 increases brain cholesterol uptake and influences neuronal structure and function

L.R. Brunham
Targeted delivery of proteins across the blood-brain barrier

I.M. Verma
Regulation of oleoyl-CoA synthesis in the peripheral nervous system: demonstration of a link with myelin synthesis

C. Cassagne
Changes in fatty acid composition of peripheral nerve myelin in essential fatty acid deficiency

P.J. Dyck
Slow recovery of the fatty acid composition of sciatic nerve in rats fed a diet initially low in n-3 fatty acids

G. Pascal
A simple and universal method for the separation and identification of phospholipid molecular species

J.F. Brouwers
The lipid composition of rat-liver plasma membranes

G.M. Gray
Lipid composition of rat liver plasma membranes

F.M. Archibald
Cerebrotendinous xanthomatosis: possible higher prevalence than previously recognized

J.K. Fink
Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis

M.R. Hayden
Leukodystrophy incidence in Germany

A. Kohlschutter
The incidence and genetics of metachromatic leucodystrophy in northern Sweden

B. Hagberg
The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease

E.H. Schuchman
Sjogren-Larsson syndrome in Sweden. A clinical, genetic and epidemiological study

G. Holmgren
Disorders of peroxisome biogenesis

H.W. Moser
X-linked adrenoleukodystrophy: clinical, biochemical and pathogenetic aspects

J. Gartner
Canavan disease: carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay

T.L. Stockley
Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form

M. Lambert

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Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

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Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

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