Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 7-Day Trial for You or Your Team.

Learn More →

Niemann-Pick Type C Disease and Intracellular Cholesterol Trafficking *

Niemann-Pick Type C Disease and Intracellular Cholesterol Trafficking * THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 280, No. 22, Issue of June 3, pp. 20917–20920, 2005 Minireview © 2005 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. dition to the SSD, a cysteine-rich luminal loop between TMD 8 Niemann-Pick Type C Disease and 9 (8) and the region between amino acids 1038 and 1253 and Intracellular Cholesterol are also important for NPC1 function (9). NPC1 protein is predominantly located within the late en- Trafficking* dosomal membrane but is also transiently associated with ly- sosomes and the trans-Golgi network (10). Multiple peptide Published, JBC Papers in Press, April 14, 2005, sequences within the protein are responsible for targeting to DOI 10.1074/jbc.R400040200 the endosomal compartment (11). Late endosomes are com- Ta-Yuan Chang‡§, Patrick C. Reid , prised of limiting membranes and internal membranes (12). Shigeki Sugii , Nobutaka Ohgami‡, The exact location of the NPC1 protein in the late endosomal Jonathan C. Cruz**, and Catherine C. Y. Chang‡ membranes is not known. From the ‡Department of Biochemistry, Dartmouth NPC2 is a soluble lysosomal protein that can be secreted Medical School, Hanover, New Hampshire 03755, from cells. It uses mannose 6-phosphate marker for targeting ¶Department of Molecular Biology and Medicine, to the late endosome (13) and is a high affinity cholesterol- RCAST, University of Tokyo, Tokyo 153-8904, Japan, binding protein (14). NPC2 also binds fatty acids in vitro but Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, with lower affinity (14). A crystal structure in the ligand free La Jolla, California 92037, and **Department of state shows that the protein has three small hydrophobic cav- Pathology, Howard Hughes Medical Institute, Harvard ities that form a “gate,” which may represent the incipient Medical School, Boston, Massachusetts 02115 cholesterol-binding site that dilates to accommodate the cholesterol molecule; the gate involves tyrosine 100 and phenylalanine 66 (15). Niemann-Pick type C (NPC) disease is a rare neurovisceral disorder characterized by progressive hepatosplenomegaly and Roles of NPC1 and NPC2 in Endosomal/Lysosomal central nervous system neurodegeneration (reviewed in Ref. 1). Lipid Trafficking The estimated prevalence is 1:150,000 individuals. The disease Low Density Lipoprotein (LDL)-derived Cholesterol—In involves the accumulation of unesterified cholesterol, sphingo- mammalian cells, LDL, the principal cholesterol carrier in the lipids, and other lipids within cells of the endosomal/lysosomal blood, binds to the LDL receptor, internalizes, and enters the system, various tissues, and the brain. The disease is autoso- endocytic compartment. There, its main cargo, comprised of mal recessive and is caused by mutations in one of two genetic cholesteryl esters, is dissimilated by hydrolysis to cholesterol loci, npc1 and npc2. Mutations in npc1 account for 95% of NPC and fatty acids. Hydrolysis of cholesteryl esters requires the cases. Affected individuals usually die before adulthood. Cur- enzyme acid lipase. In tissue culture cells, most of the lipase is rently there is no cure; however, new biochemical insight has located in endocytic compartments that are distinct from the provided clues to how to slow the disease. late endosomes/lysosomes; after lipase action, the liberated cholesterol appears in the late endosomes/lysosomes (16). In Biochemical Studies on NPC1 and NPC2 Proteins NPC1 cells (i.e. cells affected by the NPC1 mutation), the trans- The human NPC1 encodes a 1278-amino acid (170–190 kDa) port of cholesterol from the late endosomes to various destina- glycoprotein with 13 putative transmembrane domains, includ- tions, including the plasma membrane, is defective (17). At ing a conserved “sterol-sensing domain” (SSD) located between present, it is not clear how NPC1 and NPC2 work in concert to the third and seventh transmembrane domains. SSDs consist transport cholesterol. of 180 amino acids organized in five consecutive transmem- Oxysterols play an important role in mediating cellular cho- brane domains. The SSD is found in several other polytopic lesterol homeostasis. Cells produce more oxysterols when cul- membrane proteins that are involved in cellular cholesterol tured in the presence of LDL, and this production is decreased homeostasis (2), cell-cell signaling (3), and the dietary uptake in cells overexpressing NPC1 and NPC2 (18). These results of cholesterol (4). SSDs are needed for NPC1 protein to function suggest that NPC1 and NPC2 may participate in delivering in intact cells (5). Binding occurs between NPC1 and a photo- LDL-derived cholesterol to proper cellular site(s) for conversion activable analog of cholesterol (azocholestanol); the binding is to oxysterols. partially blocked by cholesterol and is much diminished in Sterols Synthesized from Acetate—In mammals, extra- NPC1 proteins that contain mutations within the SSD (6). hepatic tissues synthesize as much cholesterol as the liver (19). Thus, one function of the SSD in NPC1 protein is to mediate In Chinese hamster ovary cells and human fibroblast cells, sterol binding. NPC1 may work as a lipid permease (7); how- biosynthesis of sterols takes place at the endoplasmic reticu- ever, the substrate specificity and the role of the SSD in medi- lum (ER). After synthesis, most sterols are rapidly transported ating permease activity have not yet been determined. In ad- from the ER to the caveolae/lipid raft domain of the plasma membrane (PM) in an energy-dependent manner. This process * This minireview will be reprinted in the 2005 Minireview Compen- does not require NPC1 (20). After reaching the PM, the newly dium, which will be available in January, 2006. This work was sup- synthesized sterol may recycle rapidly (within minutes) be- ported by National Institutes of Health Grant R01 HL36709. tween the PM and the recycling endosome (21). After 8 or more § To whom correspondence should be addressed: Dept. of Biochemis- hours, the endogenously synthesized sterols accumulate in the try, Dartmouth Medical School, 7200 Vail, Rm. 304, Hanover, NH 03755. Tel.: 603-650-1622; Fax: 603-650-1128; E-mail: Ta.Yuan. late endosomal/lysosomal compartment of NPC1 cells but not [email protected]. in normal cells. The recycling of these sterols from the late The abbreviations used are: NPC, Niemann-Pick type C; SSD, ste- endosomes to the PM, and the esterification of these molecules rol-sensing domain; TMD, transmembrane domain; LDL, low density within the ER are also partially defective in NPC1 cells (22– lipoprotein; ER, endoplasmic reticulum; PM, plasma membrane; NB- DNJ, N-butyl deoxynojirimycin; PND, postnatal day. 24). The effect of NPC1 on trafficking of endogenously synthe- This paper is available on line at http://www.jbc.org 20917 This is an Open Access article under the CC BY license. 20918 Minireview: NPC and Cholesterol Trafficking FIG.1. Cholesterol accumulation in Purkinje neurons of NPC1 mice at post- natal day 9. Cerebellar brain sections from NIH PND 9 NPC1 (BALB/c NPC1 ) mice and WT mice were stained with the cholesterol binding agent BC-theta (red) and anti-Cal- bindin antibodies (a Purkinje cell marker protein; blue). Main panel, NPC1 Purkinje dendrite, cholesterol accumulation indicated by arrows, scale bar is 5 m; lower left panel, NPC1 Purkinje cell body, indicated by aster- isk; lower right panel, WT Purkinje dendrite, scale bar is 10 m. Reproduced with permis- sion from Reid et al. (53). sized sterols is cell-type dependent: macrophages and glial cells another raft lipid (36). In addition, it has been shown that in are prominently affected by the NPC1 mutation, whereas em- NPC1 cells endosomal/lysosomal cholesterol accumulation bryonic fibroblasts are less affected (25, 26). causes inhibition of lysosomal sphingomyelinase (37) and lyso- Sterol Synthesis, Transport, and Secretion in Brain Cells—In somal glucosylceramidase (the enzymes responsible for degrad- mammals, the brain contains more unesterified cholesterol, ing sphingomyelin and glucosylceramides) (38). The lower glu- most of which is acquired by endogenous synthesis, than any cosylceramidase activity in NPC1 cells has been attributed to other organ in the body (27). Both neurons and astrocytes mislocalization of the enzyme due to cholesterol loading. It is isolated from the NPC1 mouse exhibit trafficking defects in also possible that, in addition to cholesterol trafficking, NPC1 exogenously provided cholesterol and endogenously synthe- may also be involved in sphingolipid recycling. Studies in yeast sized sterol (28–30, 25). Despite these defects, NPC1 mouse show that a mutation in the sterol-sensing domain of NPC1 astrocytes synthesize and secrete the NPC2 and apolipoprotein results in defective recycling, localization, and increased quan- E proteins (31, 32). tities of complex glycosphingolipids, without obvious changes Glycosphingolipids and Other Lipids—In addition to choles- in sterol metabolism (39). terol, various other lipids, such as sphingomyelin, glucosylcer- Endosomal Cholesterol and Rab Proteins—Various abnor- amide, certain gangliosides (especially GM2 and GM3), and malities can cause endosomal cholesterol to accumulate and lysobisphosphatidic acid, also accumulate in NPC1 cells (1). perturb the functions of Rab7 and Rab4 proteins. Late endo- Gangliosides are acidic glycosphingolipids that are normally somes and lysosomes exhibit bidirectional motility, moving present in cell membranes at high levels. Mutations in genes back and forth between the periphery and the pericentriolar encoding enzymes or proteins involved in the catabolism of region of cells. Endosomal motility is controlled in part by Rab glycosphingolipids cause various glycosphingolipids to accumu- proteins, small GTPases that are intimately involved in vari- late within lysosomes, leading to secondary cholesterol accu- ous membrane trafficking events. Rab7 and the related Rab9 mulation (33, 34). N-Butyl deoxynojirimycin (NB-DNJ) is an are located in the late endosomes. Rab7 interacts more with inhibitor of the enzyme glucosylceramide synthetase, a key earlier endosomes and lysosomes, whereas Rab9 interacts more enzyme involved in the biosynthesis of gangliosides in animal with the trans-Golgi (40). Rab4 is located in early endosomes. cells. In NPC1 cells, some of the endosomal malfunction can be Mammalian cells treated with the hydrophobic amine “U-drug” corrected by treating cells with NB-DNJ (35); however, the or cells doubly deficient in the major late endosomal/lysosomal drug has little effect on reversing the cholesterol trafficking membrane proteins Lamp1/Lamp2, exhibit significantly re- defect (22, 35). Thus, it is unlikely that the cholesterol traffick- duced motility of the late endosomes, accumulate endosomal ing defects observed in NPC1 cells are due to secondary conse- cholesterol, and exhibit NPC-like phenotypes (41, 42). The quence of glycosphingolipid accumulation. above observations may be explained by cholesterol accumula- The accumulation of glycosphingolipid in NPC1 cells may be tion due to various endosomal abnormalities, leading in turn to explained by the high affinity between cholesterol and sphin- the inhibition of Rab7 and Rab4 (42, 43). The inhibition of Rab7 golipids, which are the major components of lipid microdo- reduces the motility of the late endosomes (42). Strikingly, mains or “rafts.” Accumulation of one raft lipid in late endo- overexpressing Rab9 corrects the lipid trafficking defects in somes/lysosomes may lead to the trapping and accumulation of NPC1 cells (44, 45). Despite the predicted pleiotropic effect of Minireview: NPC and Cholesterol Trafficking 20919 overexpressing certain Rab proteins, this procedure may pro- postnatal NPC1 mice delays the onset of neurological symp- vide novel therapeutic treatment of NPC disease, which is fatal toms, increases Purkinje and granule cell survival, reduces and currently has no cure. cortical GM2 and GM3 ganglioside accumulation, and doubles Mutations in Other Proteins That Produce an NPC-like Phe- the lifespan of the treated NPC1 mice. Most impressively, a notype—Several other proteins residing in late endosomes/ly- single injection at PND 7 provides the most effective treatment sosomes, including MLN64 and MENTHO (46), may also be to NPC1 mice (62). involved in endosomal cholesterol movement. The role of Conclusion MLN64 in sterol trafficking is not clear because mice with Much is yet to be learned about lipid trafficking in general. targeted mutation of MLN64 are healthy and display only Abnormalities in endosomal lipid transport have serious con- minimal disturbances in sterol dynamics (47). A novel CHO cell sequences, especially in the brain. Future NPC-related re- mutant without the NPC1 mutation but with defects in late search will provide insight into cellular lipid trafficking and the endosomal cholesterol trafficking has been isolated (48). etiology of the disease. ABCA1 is a key protein that mediates apoA-I-dependent sterol efflux. In cells lacking ABCA1, cholesterol and sphingomyelin Acknowledgments—We thank Helina Morgan and Ellen Chang for accumulate in abnormally structured late endocytic vesicles, careful editing of the manuscript. and these lipids exhibit impaired intracellular movement (49). REFERENCES Two cell models for the disease cystic fibrosis (50), and fibro- 1. Patterson, M. C., Vanier, M. T., Suzuki, K., Morris, J. A., Carstea, E., Neufeld, blast cells with mutations in the 3-hydroxysteroid (7)-reduc- E. B., Blanchette-Mackie, J. E., and Pentchev, P. G. (2001) in The Metabolic tase gene (51), also accumulate intracellular cholesterol in a and Molecular Bases of Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds) 8th Ed., Vol. 3, pp. 3611–3633, McGraw-Hill, New manner similar to NPC1 cells. York 2. Radhakrishnan, A., Sun, L. P., Kwon, H. J., Brown, M. S., and Goldstein, J. L. Neuropathological Studies (2004) Mol. Cell 15, 259–268 NIH 3. Kuwabara, P. E., and Labouesse, M. (2002) Trends Genet. 18, 193–201 The mouse model for NPC disease, the BALB/c NPC1 4. Altmann, S. W., Davis, H. R. J., Zhu, L. J., Yao, X., Hoos, L. M., Tetzloff, G., mouse (designated as the NPC1 mouse), has a well defined Iyer, S. P., Maguire, M., Golovko, A., Zeng, M., Wang, L., Murgolo, N., and Graziano, M. P. (2004) Science 303, 1201–1204 mutation in the npc1 gene and exhibits clinical phenotypes 5. Ko, D. C., Gordon, M. D., Jin, J. Y., and Scott, M. P. (2001) Mol. Biol. Cell 12, very similar to those of human NPC disease (1). In 30-postnatal 601–614 day (PND) NPC1 mice, Purkinje neurons of the cerebellum 6. Ohgami, N., Ko, D. C., Thomas, M., Scott, M. P., Chang, C. C., and Chang, T. Y. (2004) Proc. Natl. Acad. Sci. U. S. A. 101, 12473–12478 undergo significant death, a hallmark of NPC disease. Many 7. Davies, J. P., Chen, F. W., and Ioannou, Y. A. (2000) Science 290, 2295–2298 other abnormalities have been reported in very young NPC1 8. Watari, H., Blanchette-Mackie, E. J., Dwyer, N. K., Watari, M., Burd, C. G., Patel, S., Pentchev, P. G., and Strauss, J. F., III (2000) Exp. Cell Res. 259, mice. Starting at PND 9, mild abnormalities occur in the corpus 247–256 callosum, cerebellar white matter, and nerve fibers (52). Also, 9. Park, W. D., O’Brien, J. F., Lundquist, P. A., Kraft, D. L., Vockley, C. W., neuronal cholesterol accumulation occurs in various regions of Karnes, P. S., Patterson, M. C., and Snow, K. (2003) Hum. Mutat. 22, 313–325 the brain (53) (Fig. 1). At PND 10, hypomyelination and axonal 10. Zhang, M., Dwyer, N. K., Neufeld, E. B., Love, D. C., Cooney, A., Comly, M., spheroids (indicative of axonal injury) in the corpus callosum Patel, S., Watari, H., Strauss, J. F., III, Pentchev, P. G., Hanover, J. A., and Blanchette-Mackie, E. J. (2001) J. Biol. Chem. 276, 3417–3425 and subcortical white matter are observed (54). By PND 22, 11. Scott, C., Higgins, M. E., Davies, J. P., and Ioannou, Y. A. (2004) J. Biol. Chem. activated astrocytes become abundant in selective regions; 279, 48214–48223 12. Kobayashi, T., Beuchat, M.-H., Chevallier, J., Makino, A., Mayran, N., Escola, these cells also accumulate intracellular cholesterol (53). At J.-M., Lebrand, C., Cosson, P., Kobayashi, T., and Gruenberg, J. (2002) this stage, significant GM2 and GM3 also accumulate in vari- J. Biol. Chem. 277, 32157–32164 ous cells (55); both astrocyte cells in corpus callosum and Pur- 13. Naureckiene, S., Sleat, D. E., Lackland, H., Fensom, A., Vanier, M. T., Watti- aux, R., Jadot, M., and Lobel, P. (2000) Science 290, 2298–2301 kinje cells in the cerebellum suffer significant cell loss (48 and 14. Ko, D. C., Binkley, J., Sidow, A., and Scott, M. P. (2003) Proc. Natl. Acad. Sci. 13%, respectively) (56). Between 4 and 6 weeks, clinical symp- U. S. A. 100, 2518–2525 toms develop. At the 7th week, severe losses in myelin protein 15. Friedland, N., Liu, H. L., Lobel, P., and Stock, A. M. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 2512–2517 and cholesterol occur (57). Death occurs between the 10th and 16. Sugii, S., Reid, P. C., Ohgami, N., Du, H., and Chang, T. Y. (2003) J. Biol. 12th weeks. The neurodegeneration in the NPC1 mice can be Chem. 278, 27180–27189 17. Wojtanik, K. M., and Liscum, L. (2003) J. Biol. Chem. 278, 14850–14856 prevented by transgenic expression of a NPC1 cDNA that ex- 18. Frolov, A., Zielinski, S. E., Crowley, J. R., Dudley-Rucker, N., Schaffer, J. E., presses the functional NPC1 protein mainly in the central and Ory, D. S. (2003) J. Biol. Chem. 278, 25517–25525 19. Dietschy, J. M., Turley, S. D., and Spady, D. K. (1993) J. Lipid Res. 34, nervous system (58). 1637–1659 A mouse model for NPC2 disease, with much lower expres- 20. Liscum, L., Ruggiero, R. M., and Faust, J. R. (1989) J. Cell. Biol. 108, sion of the NPC2 protein (0–4% of normal), has been produced 1625–1636 21. Hao, M., and Maxfield, F. R. (2000) J. Biol. Chem. 275, 15279–15286 (59). In terms of disease onset, progression, pathology, neuro- 22. Cruz, J. C., and Chang, T. Y. (2000) J. Biol. Chem. 275, 41309–41316 nal storage, etc., the phenotypes of NPC1 mice, NPC2 mice, and 23. Lange, Y., Ye, J., Rigney, M., and Steck, T. (2000) J. Biol. Chem. 275, 17468–17475 NPC1:NPC2 double mutant mice are similar or identical. 24. Lange, Y., Ye, J., and Steck, T. L. (1998) J. Biol. Chem. 273, 18915–18922 25. Reid, P. C., Sugii, S., and Chang, T. Y. (2003) J. Lipid Res. 44, 1010–1019 Potential Drug Therapy 26. Reid, P. C., and Chang, T. Y. (2003) International Atherosclerosis Society (IAS) Commentary (http://www.athero.org) In terms of delaying the syndrome, two experimental drug 27. Dietschy, J. M., and Turley, S. D. (2004) J. Lipid Res. 45, 1375–1397 therapies, both tested in NPC1 mice only, have achieved lim- 28. Henderson, L. P., Lin, L., Prasad, A., Paul, C. A., Chang, T. Y., and Maue, R. A. ited success. (2000) J. Biol. Chem. 275, 20179–20187 29. Karten, B., Vance, D. E., Campenot, R. B., and Vance, J. E. (2003) J. Biol. Substrate Reduction Therapy by NB-DNJ—In animal stud- Chem. 278, 4168–4175 ies, NB-DNJ treatment in NPC1 mice and cats delays the onset 30. Karten, B., Vance, D. E., Campenot, R. B., and Vance, J. E. (2002) J. Neuro- chem. 83, 1154–1163 of clinical neurological symptoms, increases longevity of NPC1 31. Mutka, A. L., Lusa, S., Linder, M. D., Jokitalo, E., Kopra, O., Jauhiainen, M., mice by 25%, and reduces cellular pathology in the cerebellum and Ikonen, E. (2004) J. Biol. Chem. 279, 48654–48662 (60). 32. Karten, B., Hayashi, H., Francis, G. A., Campenot, R. B., Vance, D. E., and Vance, J. E. (2004) Biochem. J. 387, 779–788 Neurosteroid Therapy—Neurosteroids, which are steroids 33. Puri, V., Watanabe, R., Dominguez, M., Sun, X., Wheatley, C. L., Marks, D. L., made by brain cells, affect neuronal growth and differentiation and Pagano, R. E. (1999) Nat. Cell. Biol. 1, 386–388 34. Puri, V., Jefferson, J. R., Singh, R. D., Wheatley, C. L., Marks, D. L., and and modulate neurotransmitter receptors (reviewed in Ref. 61). Pagano, R. E. (2003) J. Biol. Chem. 278, 20961–20970 NPC1 mice at PND 48–50 contain far fewer neurosteroids than 35. te Vruchte, D., Lloyd-Evans, E., Veldman, R. J., Neville, D. C., Dwek, R. A., wild-type mice. Administration of allopregnanolone in early Platt, F. M., van Blitterswijk, W. J., and Sillence, D. J. (2004) J. Biol. Chem. 20920 Minireview: NPC and Cholesterol Trafficking 279, 26167–26175 Cooney, A., Comly, M., Dwyer, N., Blanchette-Mackie, J., Remaley, A. T., 36. Simons, K., and Gruenberg, J. (2000) Trends Cell Biol. 10, 459–462 Santamarina-Fojo, S., and Brewer, H. B., Jr. (2004) J. Biol. Chem. 279, 37. Reagan, J. W., Jr., Hubbert, M. L., and Shelness, G. S. (2000) J. Biol. Chem. 15571–15578 275, 38104–38110 50. White, N. M., Corey, D. A., and Kelley, T. J. (2004) Am. J. Respir. Cell Mol. 38. Salvioli, R., Scarpa, S., Ciaffoni, F., Tatti, M., Ramoni, C., Vanier, M. T., and Biol. 31, 538–543 Vaccaro, A. M. (2004) J. Biol. Chem. 279, 17674–17680 51. Wassif, C. A., Vied, D., Tsokos, M., Connor, W. E., Steiner, R. D., and Porter, 39. Krishnamurthy, M., Higaki, K., Tinkelenberg, A. H., Balderes, D. A., Alman- F. D. (2002) Mol. Genet. Metab. 75, 325–334 zar-Paramio, D., Wilcox, L., Erdeniz, N., Redican, F., Padamsee, M., Liu, Y., 52. Ong, W.-Y., Kumar, U., Switzer, R. C., Sidhu, A., Suresh, G., Hu, C.-Y., and Khan, S., Alcantara, F., Carstea, E. D., Morris, J. A., and Sturley, S. L. Patel, S. C. (2001) Exp. Brain Res. 141, 218–231 (2004) J. Cell Biol. 164, 547–556 53. Reid, P. C., Sakashita, N., Sugii, S., Ohno-Iwashita, Y., Shimada, Y., Hickey, 40. Pfeffer, S., and Aivazian, D. (2004) Nat. Rev. Mol. Cell. Biol. 5, 886–896 W. F., and Chang, T. Y. (2004) J. Lipid Res. 45, 582–591 41. Eskelinen, E. L., Schmidt, C. K., Neu, S., Willenborg, M., Fuertes, G., Salva- 54. Takikita, S., Fukuda, T., Mohri, I., Yagi, T., and Suzuki, K. (2004) J. Neuro- dor, N., Tanaka, Y., Lullmann-Rauch, R., Hartmann, D., Heeren, J., von pathol. Exp. Neurol. 63, 660–673 Figura, K., Knecht, E., and Saftig, P. (2004) Mol. Biol. Cell 15, 3132–3145 55. Zervas, M., Dobrenis, K., and Walkley, S. U. (2001) J. Neuropathol. Exp. 42. Lebrand, C., Corti, M., Goodson, H., Cosson, P., Cavalli, V., Mayran, N., Faure, Neurol. 60, 49–64 J., and Gruenberg, J. (2002) EMBO J. 21, 1289–1300 56. German, D. C., Liang, C. L., Song, T., Yazdani, U., Xie, C., and Dietschy, J. M. 43. Choudhury, A., Sharma, D. K., Marks, D. L., and Pagano, R. E. (2004) Mol. (2002) Neuroscience 109, 437–450 Biol. Cell 15, 4500–4511 57. Xie, C., Burns, D. K., Turley, S. D., and Dietschy, J. M. (2000) J. Neuropathol. 44. Choudhury, A., Dominguez, M., Puri, V., Sharma, D. K., Narita, K., Wheatley, Exp. Neurol. 59, 1106–1117 C. L., Marks, D. L., and Pagano, R. E. (2002) J. Clin. Invest. 109, 1541–1550 58. Loftus, S. K., Erickson, R. P., Walkley, S. U., Bryant, M. A., Incao, A., Hei- 45. Walter, M., Davies, J. P., and Ioannou, Y. A. (2003) J. Lipid Res. 44, 243–253 denreich, R. A., and Pavan, W. J. (2002) Hum. Mol. Genet. 11, 3107–3114 46. Alpy, F., Wendling, C., Rio, M. C., and Tomasetto, C. (2002) J. Biol. Chem. 277, 59. Sleat, D. E., Wiseman, J. A., El-Banna, M., Price, S. M., Verot, L., Shen, M. M., 50780–50787 Tint, G. S., Vanier, M. T., Walkley, S. U., and Lobel, P. (2004) Proc. Natl. 47. Kishida, T., Kostetskii, I., Zhang, Z., Martinez, F., Liu, P., Walkley, S. U., Acad. Sci. U. S. A. 101, 5886–5891 Dwyer, N. K., Blanchette-Mackie, E. J., Radice, G. L., and Strauss, J. F., III 60. Zervas, M., Somers, K. L., Thrall, M. A., and Walkley, S. U. (2001) Curr. Biol. (2004) J. Biol. Chem. 279, 19276–19285 11, 1283–1287 48. Frolov, A., Srivastava, K., Daphna-Iken, D., Traub, L. M., Schaffer, J. E., and 61. Compagnone, N. A., and Mellon, S. H. (2000) Front Neuroendocrinol. 21, 1–56 Ory, D. S. (2001) J. Biol. Chem. 276, 46414–46421 62. Griffin, L. D., Gong, W., Verot, L., and Mellon, S. H. (2004) Nat. Med. 10, 49. Neufeld, E. B., Stonik, J. A., Demosky, S. J., Jr., Knapper, C. L., Combs, C. A., 704–711 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Biological Chemistry American Society for Biochemistry and Molecular Biology

Niemann-Pick Type C Disease and Intracellular Cholesterol Trafficking *

Download PDF
4 pages

Loading next page...
 
/lp/american-society-for-biochemistry-and-molecular-biology/niemann-pick-type-c-disease-and-intracellular-cholesterol-trafficking-pme6jJcWuw

References (65)

Publisher
American Society for Biochemistry and Molecular Biology
Copyright
Copyright © 2005 Elsevier Inc.
ISSN
0021-9258
eISSN
1083-351X
DOI
10.1074/jbc.r400040200
Publisher site
See Article on Publisher Site

Abstract

THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 280, No. 22, Issue of June 3, pp. 20917–20920, 2005 Minireview © 2005 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. dition to the SSD, a cysteine-rich luminal loop between TMD 8 Niemann-Pick Type C Disease and 9 (8) and the region between amino acids 1038 and 1253 and Intracellular Cholesterol are also important for NPC1 function (9). NPC1 protein is predominantly located within the late en- Trafficking* dosomal membrane but is also transiently associated with ly- sosomes and the trans-Golgi network (10). Multiple peptide Published, JBC Papers in Press, April 14, 2005, sequences within the protein are responsible for targeting to DOI 10.1074/jbc.R400040200 the endosomal compartment (11). Late endosomes are com- Ta-Yuan Chang‡§, Patrick C. Reid , prised of limiting membranes and internal membranes (12). Shigeki Sugii , Nobutaka Ohgami‡, The exact location of the NPC1 protein in the late endosomal Jonathan C. Cruz**, and Catherine C. Y. Chang‡ membranes is not known. From the ‡Department of Biochemistry, Dartmouth NPC2 is a soluble lysosomal protein that can be secreted Medical School, Hanover, New Hampshire 03755, from cells. It uses mannose 6-phosphate marker for targeting ¶Department of Molecular Biology and Medicine, to the late endosome (13) and is a high affinity cholesterol- RCAST, University of Tokyo, Tokyo 153-8904, Japan, binding protein (14). NPC2 also binds fatty acids in vitro but Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, with lower affinity (14). A crystal structure in the ligand free La Jolla, California 92037, and **Department of state shows that the protein has three small hydrophobic cav- Pathology, Howard Hughes Medical Institute, Harvard ities that form a “gate,” which may represent the incipient Medical School, Boston, Massachusetts 02115 cholesterol-binding site that dilates to accommodate the cholesterol molecule; the gate involves tyrosine 100 and phenylalanine 66 (15). Niemann-Pick type C (NPC) disease is a rare neurovisceral disorder characterized by progressive hepatosplenomegaly and Roles of NPC1 and NPC2 in Endosomal/Lysosomal central nervous system neurodegeneration (reviewed in Ref. 1). Lipid Trafficking The estimated prevalence is 1:150,000 individuals. The disease Low Density Lipoprotein (LDL)-derived Cholesterol—In involves the accumulation of unesterified cholesterol, sphingo- mammalian cells, LDL, the principal cholesterol carrier in the lipids, and other lipids within cells of the endosomal/lysosomal blood, binds to the LDL receptor, internalizes, and enters the system, various tissues, and the brain. The disease is autoso- endocytic compartment. There, its main cargo, comprised of mal recessive and is caused by mutations in one of two genetic cholesteryl esters, is dissimilated by hydrolysis to cholesterol loci, npc1 and npc2. Mutations in npc1 account for 95% of NPC and fatty acids. Hydrolysis of cholesteryl esters requires the cases. Affected individuals usually die before adulthood. Cur- enzyme acid lipase. In tissue culture cells, most of the lipase is rently there is no cure; however, new biochemical insight has located in endocytic compartments that are distinct from the provided clues to how to slow the disease. late endosomes/lysosomes; after lipase action, the liberated cholesterol appears in the late endosomes/lysosomes (16). In Biochemical Studies on NPC1 and NPC2 Proteins NPC1 cells (i.e. cells affected by the NPC1 mutation), the trans- The human NPC1 encodes a 1278-amino acid (170–190 kDa) port of cholesterol from the late endosomes to various destina- glycoprotein with 13 putative transmembrane domains, includ- tions, including the plasma membrane, is defective (17). At ing a conserved “sterol-sensing domain” (SSD) located between present, it is not clear how NPC1 and NPC2 work in concert to the third and seventh transmembrane domains. SSDs consist transport cholesterol. of 180 amino acids organized in five consecutive transmem- Oxysterols play an important role in mediating cellular cho- brane domains. The SSD is found in several other polytopic lesterol homeostasis. Cells produce more oxysterols when cul- membrane proteins that are involved in cellular cholesterol tured in the presence of LDL, and this production is decreased homeostasis (2), cell-cell signaling (3), and the dietary uptake in cells overexpressing NPC1 and NPC2 (18). These results of cholesterol (4). SSDs are needed for NPC1 protein to function suggest that NPC1 and NPC2 may participate in delivering in intact cells (5). Binding occurs between NPC1 and a photo- LDL-derived cholesterol to proper cellular site(s) for conversion activable analog of cholesterol (azocholestanol); the binding is to oxysterols. partially blocked by cholesterol and is much diminished in Sterols Synthesized from Acetate—In mammals, extra- NPC1 proteins that contain mutations within the SSD (6). hepatic tissues synthesize as much cholesterol as the liver (19). Thus, one function of the SSD in NPC1 protein is to mediate In Chinese hamster ovary cells and human fibroblast cells, sterol binding. NPC1 may work as a lipid permease (7); how- biosynthesis of sterols takes place at the endoplasmic reticu- ever, the substrate specificity and the role of the SSD in medi- lum (ER). After synthesis, most sterols are rapidly transported ating permease activity have not yet been determined. In ad- from the ER to the caveolae/lipid raft domain of the plasma membrane (PM) in an energy-dependent manner. This process * This minireview will be reprinted in the 2005 Minireview Compen- does not require NPC1 (20). After reaching the PM, the newly dium, which will be available in January, 2006. This work was sup- synthesized sterol may recycle rapidly (within minutes) be- ported by National Institutes of Health Grant R01 HL36709. tween the PM and the recycling endosome (21). After 8 or more § To whom correspondence should be addressed: Dept. of Biochemis- hours, the endogenously synthesized sterols accumulate in the try, Dartmouth Medical School, 7200 Vail, Rm. 304, Hanover, NH 03755. Tel.: 603-650-1622; Fax: 603-650-1128; E-mail: Ta.Yuan. late endosomal/lysosomal compartment of NPC1 cells but not [email protected]. in normal cells. The recycling of these sterols from the late The abbreviations used are: NPC, Niemann-Pick type C; SSD, ste- endosomes to the PM, and the esterification of these molecules rol-sensing domain; TMD, transmembrane domain; LDL, low density within the ER are also partially defective in NPC1 cells (22– lipoprotein; ER, endoplasmic reticulum; PM, plasma membrane; NB- DNJ, N-butyl deoxynojirimycin; PND, postnatal day. 24). The effect of NPC1 on trafficking of endogenously synthe- This paper is available on line at http://www.jbc.org 20917 This is an Open Access article under the CC BY license. 20918 Minireview: NPC and Cholesterol Trafficking FIG.1. Cholesterol accumulation in Purkinje neurons of NPC1 mice at post- natal day 9. Cerebellar brain sections from NIH PND 9 NPC1 (BALB/c NPC1 ) mice and WT mice were stained with the cholesterol binding agent BC-theta (red) and anti-Cal- bindin antibodies (a Purkinje cell marker protein; blue). Main panel, NPC1 Purkinje dendrite, cholesterol accumulation indicated by arrows, scale bar is 5 m; lower left panel, NPC1 Purkinje cell body, indicated by aster- isk; lower right panel, WT Purkinje dendrite, scale bar is 10 m. Reproduced with permis- sion from Reid et al. (53). sized sterols is cell-type dependent: macrophages and glial cells another raft lipid (36). In addition, it has been shown that in are prominently affected by the NPC1 mutation, whereas em- NPC1 cells endosomal/lysosomal cholesterol accumulation bryonic fibroblasts are less affected (25, 26). causes inhibition of lysosomal sphingomyelinase (37) and lyso- Sterol Synthesis, Transport, and Secretion in Brain Cells—In somal glucosylceramidase (the enzymes responsible for degrad- mammals, the brain contains more unesterified cholesterol, ing sphingomyelin and glucosylceramides) (38). The lower glu- most of which is acquired by endogenous synthesis, than any cosylceramidase activity in NPC1 cells has been attributed to other organ in the body (27). Both neurons and astrocytes mislocalization of the enzyme due to cholesterol loading. It is isolated from the NPC1 mouse exhibit trafficking defects in also possible that, in addition to cholesterol trafficking, NPC1 exogenously provided cholesterol and endogenously synthe- may also be involved in sphingolipid recycling. Studies in yeast sized sterol (28–30, 25). Despite these defects, NPC1 mouse show that a mutation in the sterol-sensing domain of NPC1 astrocytes synthesize and secrete the NPC2 and apolipoprotein results in defective recycling, localization, and increased quan- E proteins (31, 32). tities of complex glycosphingolipids, without obvious changes Glycosphingolipids and Other Lipids—In addition to choles- in sterol metabolism (39). terol, various other lipids, such as sphingomyelin, glucosylcer- Endosomal Cholesterol and Rab Proteins—Various abnor- amide, certain gangliosides (especially GM2 and GM3), and malities can cause endosomal cholesterol to accumulate and lysobisphosphatidic acid, also accumulate in NPC1 cells (1). perturb the functions of Rab7 and Rab4 proteins. Late endo- Gangliosides are acidic glycosphingolipids that are normally somes and lysosomes exhibit bidirectional motility, moving present in cell membranes at high levels. Mutations in genes back and forth between the periphery and the pericentriolar encoding enzymes or proteins involved in the catabolism of region of cells. Endosomal motility is controlled in part by Rab glycosphingolipids cause various glycosphingolipids to accumu- proteins, small GTPases that are intimately involved in vari- late within lysosomes, leading to secondary cholesterol accu- ous membrane trafficking events. Rab7 and the related Rab9 mulation (33, 34). N-Butyl deoxynojirimycin (NB-DNJ) is an are located in the late endosomes. Rab7 interacts more with inhibitor of the enzyme glucosylceramide synthetase, a key earlier endosomes and lysosomes, whereas Rab9 interacts more enzyme involved in the biosynthesis of gangliosides in animal with the trans-Golgi (40). Rab4 is located in early endosomes. cells. In NPC1 cells, some of the endosomal malfunction can be Mammalian cells treated with the hydrophobic amine “U-drug” corrected by treating cells with NB-DNJ (35); however, the or cells doubly deficient in the major late endosomal/lysosomal drug has little effect on reversing the cholesterol trafficking membrane proteins Lamp1/Lamp2, exhibit significantly re- defect (22, 35). Thus, it is unlikely that the cholesterol traffick- duced motility of the late endosomes, accumulate endosomal ing defects observed in NPC1 cells are due to secondary conse- cholesterol, and exhibit NPC-like phenotypes (41, 42). The quence of glycosphingolipid accumulation. above observations may be explained by cholesterol accumula- The accumulation of glycosphingolipid in NPC1 cells may be tion due to various endosomal abnormalities, leading in turn to explained by the high affinity between cholesterol and sphin- the inhibition of Rab7 and Rab4 (42, 43). The inhibition of Rab7 golipids, which are the major components of lipid microdo- reduces the motility of the late endosomes (42). Strikingly, mains or “rafts.” Accumulation of one raft lipid in late endo- overexpressing Rab9 corrects the lipid trafficking defects in somes/lysosomes may lead to the trapping and accumulation of NPC1 cells (44, 45). Despite the predicted pleiotropic effect of Minireview: NPC and Cholesterol Trafficking 20919 overexpressing certain Rab proteins, this procedure may pro- postnatal NPC1 mice delays the onset of neurological symp- vide novel therapeutic treatment of NPC disease, which is fatal toms, increases Purkinje and granule cell survival, reduces and currently has no cure. cortical GM2 and GM3 ganglioside accumulation, and doubles Mutations in Other Proteins That Produce an NPC-like Phe- the lifespan of the treated NPC1 mice. Most impressively, a notype—Several other proteins residing in late endosomes/ly- single injection at PND 7 provides the most effective treatment sosomes, including MLN64 and MENTHO (46), may also be to NPC1 mice (62). involved in endosomal cholesterol movement. The role of Conclusion MLN64 in sterol trafficking is not clear because mice with Much is yet to be learned about lipid trafficking in general. targeted mutation of MLN64 are healthy and display only Abnormalities in endosomal lipid transport have serious con- minimal disturbances in sterol dynamics (47). A novel CHO cell sequences, especially in the brain. Future NPC-related re- mutant without the NPC1 mutation but with defects in late search will provide insight into cellular lipid trafficking and the endosomal cholesterol trafficking has been isolated (48). etiology of the disease. ABCA1 is a key protein that mediates apoA-I-dependent sterol efflux. In cells lacking ABCA1, cholesterol and sphingomyelin Acknowledgments—We thank Helina Morgan and Ellen Chang for accumulate in abnormally structured late endocytic vesicles, careful editing of the manuscript. and these lipids exhibit impaired intracellular movement (49). REFERENCES Two cell models for the disease cystic fibrosis (50), and fibro- 1. Patterson, M. C., Vanier, M. T., Suzuki, K., Morris, J. A., Carstea, E., Neufeld, blast cells with mutations in the 3-hydroxysteroid (7)-reduc- E. B., Blanchette-Mackie, J. E., and Pentchev, P. G. (2001) in The Metabolic tase gene (51), also accumulate intracellular cholesterol in a and Molecular Bases of Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S., and Valle, D., eds) 8th Ed., Vol. 3, pp. 3611–3633, McGraw-Hill, New manner similar to NPC1 cells. York 2. Radhakrishnan, A., Sun, L. P., Kwon, H. J., Brown, M. S., and Goldstein, J. L. Neuropathological Studies (2004) Mol. Cell 15, 259–268 NIH 3. Kuwabara, P. E., and Labouesse, M. (2002) Trends Genet. 18, 193–201 The mouse model for NPC disease, the BALB/c NPC1 4. Altmann, S. W., Davis, H. R. J., Zhu, L. J., Yao, X., Hoos, L. M., Tetzloff, G., mouse (designated as the NPC1 mouse), has a well defined Iyer, S. P., Maguire, M., Golovko, A., Zeng, M., Wang, L., Murgolo, N., and Graziano, M. P. (2004) Science 303, 1201–1204 mutation in the npc1 gene and exhibits clinical phenotypes 5. Ko, D. C., Gordon, M. D., Jin, J. Y., and Scott, M. P. (2001) Mol. Biol. Cell 12, very similar to those of human NPC disease (1). In 30-postnatal 601–614 day (PND) NPC1 mice, Purkinje neurons of the cerebellum 6. Ohgami, N., Ko, D. C., Thomas, M., Scott, M. P., Chang, C. C., and Chang, T. Y. (2004) Proc. Natl. Acad. Sci. U. S. A. 101, 12473–12478 undergo significant death, a hallmark of NPC disease. Many 7. Davies, J. P., Chen, F. W., and Ioannou, Y. A. (2000) Science 290, 2295–2298 other abnormalities have been reported in very young NPC1 8. Watari, H., Blanchette-Mackie, E. J., Dwyer, N. K., Watari, M., Burd, C. G., Patel, S., Pentchev, P. G., and Strauss, J. F., III (2000) Exp. Cell Res. 259, mice. Starting at PND 9, mild abnormalities occur in the corpus 247–256 callosum, cerebellar white matter, and nerve fibers (52). Also, 9. Park, W. D., O’Brien, J. F., Lundquist, P. A., Kraft, D. L., Vockley, C. W., neuronal cholesterol accumulation occurs in various regions of Karnes, P. S., Patterson, M. C., and Snow, K. (2003) Hum. Mutat. 22, 313–325 the brain (53) (Fig. 1). At PND 10, hypomyelination and axonal 10. Zhang, M., Dwyer, N. K., Neufeld, E. B., Love, D. C., Cooney, A., Comly, M., spheroids (indicative of axonal injury) in the corpus callosum Patel, S., Watari, H., Strauss, J. F., III, Pentchev, P. G., Hanover, J. A., and Blanchette-Mackie, E. J. (2001) J. Biol. Chem. 276, 3417–3425 and subcortical white matter are observed (54). By PND 22, 11. Scott, C., Higgins, M. E., Davies, J. P., and Ioannou, Y. A. (2004) J. Biol. Chem. activated astrocytes become abundant in selective regions; 279, 48214–48223 12. Kobayashi, T., Beuchat, M.-H., Chevallier, J., Makino, A., Mayran, N., Escola, these cells also accumulate intracellular cholesterol (53). At J.-M., Lebrand, C., Cosson, P., Kobayashi, T., and Gruenberg, J. (2002) this stage, significant GM2 and GM3 also accumulate in vari- J. Biol. Chem. 277, 32157–32164 ous cells (55); both astrocyte cells in corpus callosum and Pur- 13. Naureckiene, S., Sleat, D. E., Lackland, H., Fensom, A., Vanier, M. T., Watti- aux, R., Jadot, M., and Lobel, P. (2000) Science 290, 2298–2301 kinje cells in the cerebellum suffer significant cell loss (48 and 14. Ko, D. C., Binkley, J., Sidow, A., and Scott, M. P. (2003) Proc. Natl. Acad. Sci. 13%, respectively) (56). Between 4 and 6 weeks, clinical symp- U. S. A. 100, 2518–2525 toms develop. At the 7th week, severe losses in myelin protein 15. Friedland, N., Liu, H. L., Lobel, P., and Stock, A. M. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 2512–2517 and cholesterol occur (57). Death occurs between the 10th and 16. Sugii, S., Reid, P. C., Ohgami, N., Du, H., and Chang, T. Y. (2003) J. Biol. 12th weeks. The neurodegeneration in the NPC1 mice can be Chem. 278, 27180–27189 17. Wojtanik, K. M., and Liscum, L. (2003) J. Biol. Chem. 278, 14850–14856 prevented by transgenic expression of a NPC1 cDNA that ex- 18. Frolov, A., Zielinski, S. E., Crowley, J. R., Dudley-Rucker, N., Schaffer, J. E., presses the functional NPC1 protein mainly in the central and Ory, D. S. (2003) J. Biol. Chem. 278, 25517–25525 19. Dietschy, J. M., Turley, S. D., and Spady, D. K. (1993) J. Lipid Res. 34, nervous system (58). 1637–1659 A mouse model for NPC2 disease, with much lower expres- 20. Liscum, L., Ruggiero, R. M., and Faust, J. R. (1989) J. Cell. Biol. 108, sion of the NPC2 protein (0–4% of normal), has been produced 1625–1636 21. Hao, M., and Maxfield, F. R. (2000) J. Biol. Chem. 275, 15279–15286 (59). In terms of disease onset, progression, pathology, neuro- 22. Cruz, J. C., and Chang, T. Y. (2000) J. Biol. Chem. 275, 41309–41316 nal storage, etc., the phenotypes of NPC1 mice, NPC2 mice, and 23. Lange, Y., Ye, J., Rigney, M., and Steck, T. (2000) J. Biol. Chem. 275, 17468–17475 NPC1:NPC2 double mutant mice are similar or identical. 24. Lange, Y., Ye, J., and Steck, T. L. (1998) J. Biol. Chem. 273, 18915–18922 25. Reid, P. C., Sugii, S., and Chang, T. Y. (2003) J. Lipid Res. 44, 1010–1019 Potential Drug Therapy 26. Reid, P. C., and Chang, T. Y. (2003) International Atherosclerosis Society (IAS) Commentary (http://www.athero.org) In terms of delaying the syndrome, two experimental drug 27. Dietschy, J. M., and Turley, S. D. (2004) J. Lipid Res. 45, 1375–1397 therapies, both tested in NPC1 mice only, have achieved lim- 28. Henderson, L. P., Lin, L., Prasad, A., Paul, C. A., Chang, T. Y., and Maue, R. A. ited success. (2000) J. Biol. Chem. 275, 20179–20187 29. Karten, B., Vance, D. E., Campenot, R. B., and Vance, J. E. (2003) J. Biol. Substrate Reduction Therapy by NB-DNJ—In animal stud- Chem. 278, 4168–4175 ies, NB-DNJ treatment in NPC1 mice and cats delays the onset 30. Karten, B., Vance, D. E., Campenot, R. B., and Vance, J. E. (2002) J. Neuro- chem. 83, 1154–1163 of clinical neurological symptoms, increases longevity of NPC1 31. Mutka, A. L., Lusa, S., Linder, M. D., Jokitalo, E., Kopra, O., Jauhiainen, M., mice by 25%, and reduces cellular pathology in the cerebellum and Ikonen, E. (2004) J. Biol. Chem. 279, 48654–48662 (60). 32. Karten, B., Hayashi, H., Francis, G. A., Campenot, R. B., Vance, D. E., and Vance, J. E. (2004) Biochem. J. 387, 779–788 Neurosteroid Therapy—Neurosteroids, which are steroids 33. Puri, V., Watanabe, R., Dominguez, M., Sun, X., Wheatley, C. L., Marks, D. L., made by brain cells, affect neuronal growth and differentiation and Pagano, R. E. (1999) Nat. Cell. Biol. 1, 386–388 34. Puri, V., Jefferson, J. R., Singh, R. D., Wheatley, C. L., Marks, D. L., and and modulate neurotransmitter receptors (reviewed in Ref. 61). Pagano, R. E. (2003) J. Biol. Chem. 278, 20961–20970 NPC1 mice at PND 48–50 contain far fewer neurosteroids than 35. te Vruchte, D., Lloyd-Evans, E., Veldman, R. J., Neville, D. C., Dwek, R. A., wild-type mice. Administration of allopregnanolone in early Platt, F. M., van Blitterswijk, W. J., and Sillence, D. J. (2004) J. Biol. Chem. 20920 Minireview: NPC and Cholesterol Trafficking 279, 26167–26175 Cooney, A., Comly, M., Dwyer, N., Blanchette-Mackie, J., Remaley, A. T., 36. Simons, K., and Gruenberg, J. (2000) Trends Cell Biol. 10, 459–462 Santamarina-Fojo, S., and Brewer, H. B., Jr. (2004) J. Biol. Chem. 279, 37. Reagan, J. W., Jr., Hubbert, M. L., and Shelness, G. S. (2000) J. Biol. Chem. 15571–15578 275, 38104–38110 50. White, N. M., Corey, D. A., and Kelley, T. J. (2004) Am. J. Respir. Cell Mol. 38. Salvioli, R., Scarpa, S., Ciaffoni, F., Tatti, M., Ramoni, C., Vanier, M. T., and Biol. 31, 538–543 Vaccaro, A. M. (2004) J. Biol. Chem. 279, 17674–17680 51. Wassif, C. A., Vied, D., Tsokos, M., Connor, W. E., Steiner, R. D., and Porter, 39. Krishnamurthy, M., Higaki, K., Tinkelenberg, A. H., Balderes, D. A., Alman- F. D. (2002) Mol. Genet. Metab. 75, 325–334 zar-Paramio, D., Wilcox, L., Erdeniz, N., Redican, F., Padamsee, M., Liu, Y., 52. Ong, W.-Y., Kumar, U., Switzer, R. C., Sidhu, A., Suresh, G., Hu, C.-Y., and Khan, S., Alcantara, F., Carstea, E. D., Morris, J. A., and Sturley, S. L. Patel, S. C. (2001) Exp. Brain Res. 141, 218–231 (2004) J. Cell Biol. 164, 547–556 53. Reid, P. C., Sakashita, N., Sugii, S., Ohno-Iwashita, Y., Shimada, Y., Hickey, 40. Pfeffer, S., and Aivazian, D. (2004) Nat. Rev. Mol. Cell. Biol. 5, 886–896 W. F., and Chang, T. Y. (2004) J. Lipid Res. 45, 582–591 41. Eskelinen, E. L., Schmidt, C. K., Neu, S., Willenborg, M., Fuertes, G., Salva- 54. Takikita, S., Fukuda, T., Mohri, I., Yagi, T., and Suzuki, K. (2004) J. Neuro- dor, N., Tanaka, Y., Lullmann-Rauch, R., Hartmann, D., Heeren, J., von pathol. Exp. Neurol. 63, 660–673 Figura, K., Knecht, E., and Saftig, P. (2004) Mol. Biol. Cell 15, 3132–3145 55. Zervas, M., Dobrenis, K., and Walkley, S. U. (2001) J. Neuropathol. Exp. 42. Lebrand, C., Corti, M., Goodson, H., Cosson, P., Cavalli, V., Mayran, N., Faure, Neurol. 60, 49–64 J., and Gruenberg, J. (2002) EMBO J. 21, 1289–1300 56. German, D. C., Liang, C. L., Song, T., Yazdani, U., Xie, C., and Dietschy, J. M. 43. Choudhury, A., Sharma, D. K., Marks, D. L., and Pagano, R. E. (2004) Mol. (2002) Neuroscience 109, 437–450 Biol. Cell 15, 4500–4511 57. Xie, C., Burns, D. K., Turley, S. D., and Dietschy, J. M. (2000) J. Neuropathol. 44. Choudhury, A., Dominguez, M., Puri, V., Sharma, D. K., Narita, K., Wheatley, Exp. Neurol. 59, 1106–1117 C. L., Marks, D. L., and Pagano, R. E. (2002) J. Clin. Invest. 109, 1541–1550 58. Loftus, S. K., Erickson, R. P., Walkley, S. U., Bryant, M. A., Incao, A., Hei- 45. Walter, M., Davies, J. P., and Ioannou, Y. A. (2003) J. Lipid Res. 44, 243–253 denreich, R. A., and Pavan, W. J. (2002) Hum. Mol. Genet. 11, 3107–3114 46. Alpy, F., Wendling, C., Rio, M. C., and Tomasetto, C. (2002) J. Biol. Chem. 277, 59. Sleat, D. E., Wiseman, J. A., El-Banna, M., Price, S. M., Verot, L., Shen, M. M., 50780–50787 Tint, G. S., Vanier, M. T., Walkley, S. U., and Lobel, P. (2004) Proc. Natl. 47. Kishida, T., Kostetskii, I., Zhang, Z., Martinez, F., Liu, P., Walkley, S. U., Acad. Sci. U. S. A. 101, 5886–5891 Dwyer, N. K., Blanchette-Mackie, E. J., Radice, G. L., and Strauss, J. F., III 60. Zervas, M., Somers, K. L., Thrall, M. A., and Walkley, S. U. (2001) Curr. Biol. (2004) J. Biol. Chem. 279, 19276–19285 11, 1283–1287 48. Frolov, A., Srivastava, K., Daphna-Iken, D., Traub, L. M., Schaffer, J. E., and 61. Compagnone, N. A., and Mellon, S. H. (2000) Front Neuroendocrinol. 21, 1–56 Ory, D. S. (2001) J. Biol. Chem. 276, 46414–46421 62. Griffin, L. D., Gong, W., Verot, L., and Mellon, S. H. (2004) Nat. Med. 10, 49. Neufeld, E. B., Stonik, J. A., Demosky, S. J., Jr., Knapper, C. L., Combs, C. A., 704–711

Journal

Journal of Biological Chemistry – American Society for Biochemistry and Molecular Biology

Published: Jun 3, 2005

There are no references for this article.