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Interrupted CAG expansions in ATXN2 gene expand the genetic spectrum of frontotemporal dementias

Interrupted CAG expansions in ATXN2 gene expand the genetic spectrum of frontotemporal dementias Fournier et al. Acta Neuropathologica Communications (2018) 6:41 https://doi.org/10.1186/s40478-018-0547-8 LETTER TO THE EDITOR Open Access Interrupted CAG expansions in ATXN2 gene expand the genetic spectrum of frontotemporal dementias 1† 1† 1,2 3 5 Clémence Fournier , Vincent Anquetil , Agnès Camuzat , Sandrine Stirati-Buron , Véronique Sazdovitch , 4 1,5 1,6 4,7 1 Laura Molina-Porcel , Sabrina Turbant , Daisy Rinaldi , Raquel Sánchez-Valle , Mathieu Barbier , 1,2 1,2,8 1,5 Morwena Latouche , Neuro-CEB Neuropathology Network, Giovanni Stevanin , Danielle Seilhean , 1,8 1,5 1,6* Alexis Brice , Charles Duyckaerts and Isabelle Le Ber Keywords: Frontotemporal dementia, Frontotemporal lobar degeneration, TDP-43, Ataxin 2, Amyotrophic lateral sclerosis, C9orf72, SCA2, GRN, Corticobasal degeneration, Corticobasal syndrome Spinocerebellar ataxia type 2 (SCA2) is due to a CAG carried a 39 CAG expansion interrupted by four CAA mo- repeat expansion in Ataxin-2 gene (ATXN2), encoding a tifs (CAG –CAA–CAG –CAA–CAG -CAA-CAG -CAA-- 8 4 4 9 polyglutamine (polyQ) stretch. Thirty-four or more CAG10), and a 27 CAG intermediate allele (CAG –CAA– uninterrupted (pure) CAG repeats are associated with CAG –CAA–CAG -CAA-CAG ) (Supplementary results). 4 4 8 cerebellar ataxia, slow saccades, and parkinsonism, The patient developed agrammatism, word omissions and beginning before 60 years [1]. SCA2 is associated with dysarthria, suggestive of nonfluent primary progressive neuronal loss in the cerebellum, substantia nigra, aphasia, at age 70 (Supplementary results). Brain imaging striatum and globus pallidus; and intranuclear aggrega- revealed frontal, left peri-sylvian and parietal atrophy; cere- tion of polyglutamine stretches, labelled by 1C2 bellum was normal (Fig. 1 a-d). At age 73, the association antibody, in the cerebellum [2]. When interrupted by of marked frontal executive dysfunction (planning, atten- CAA motifs, full CAG expansions produce isolated tion, inhibition, mental flexibility deficits), ideomotor levodopa-responsive parkinsonism [3]. On the other apraxia (praxis score: 4/23), akinetic-rigid parkinsonism, hand, intermediate alleles greater than 26 [4], and up to with asymmetric fronto-temporo-parietal atrophy, was con- 39 CAG repeats [5], represent a strong risk factor for sistent with a frontal-behavioral subtype of corticobasal amyotrophic lateral sclerosis (ALS) associated with neur- syndrome (CBS) [6]. He had no cerebellar syndrome. He onal TDP-43 (TAR DNA binding Protein 43) inclusions. died at age 77. No information about the patient’sfamily ATXN2 contribution to TDP-43-proteinopathies has was available. been studied mostly in ALS. We evaluated the contribu- A post-mortem examination was performed tion of ATXN2 in 31 patients with frontotemporal lobar (Supplementary methods and results). Both 39 and 27 degeneration (FTLD) and pathologically proven TDP-43 CAG alleles were found in all studied brain structures inclusions (FTLD-TDP) without known related mutation (frontal cortex, striatum, mesencephalon, occipital (Supplementary methods, Additional file 1: Table S1). cortex, cerebellum) (Additional file 1: Figure S1 and One patient (patient 5, Additional file 1: Table S1) Figure S2). Macroscopic examination revealed marked atrophy of frontal, temporal lobes, Ammon’s horn (CA1) * Correspondence: Isabelle.leber@upmc.fr and the subiculum. Neuronal loss and gliosis, associated Clémence Fournier and Vincent Anquetil contributed equally to this work. with a superficial laminar spongiosis, were severe in the Institut du Cerveau et la Moelle épinière (ICM), Sorbonne Université, UPMC superficial layers of the middle frontal gyrus, motor Univ Paris 06, Inserm U1127, CNRS UMR 7225, Hôpital Pitié-Salpêtrière, Paris, France cortex, supramarginal gyrus, CA1 and the subiculum. Department of Neurology, AP-HP - Hopital Pitié-Salpêtrière, Reference The pons (including the locus coeruleus), the cerebellum center for rare or early dementias, Institute of Memory and Alzheimer’s (Fig. 1e) and the dentate nucleus were normal. TDP-43, Disease (IM2A), Paris, France Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Fournier et al. Acta Neuropathologica Communications (2018) 6:41 Page 2 of 4 e f g h i j Fig. 1. Brain imaging and pathology. Left: Brain MRI and CT scan and HMPAO-SPECT examination of patient 5 (aged 73 years). a.Brain T1 axial sections showing marked bilateral frontal atrophy, associated with predominantly left parietal atrophy (arrows). b. T1 axial and coronal sections, showing no cerebellar atrophy. c. brain CT scan (axial sections) showing predominantly left peri-sylvian and frontal atrophy (arrows). d. HMPAO-SPECT examination (axial and coronal sections) showing bilateral, predominantly left (arrow), hypoperfusion. L: left; R: right. Right: Brain pathological lesions of patient 5. e. Cerebellum. Haematoxylin-Eosin stain. Normal density of Purkinje cells, of granule cells and of glomeruli. f. Dentate gyrus. Phospho-TDP-43 immunohistochemistry. Neuronal cytoplasmic inclusion. g. Upper layers of the middle frontal gyrus. Phospho-TDP-43 immunohistochemistry. Several cytoplasmic inclusions (short arrows) in glial cells. One phospho-TDP-43 positive neurite (long arrow). h. Middle frontal gyrus. Phospho-TDP-43immunohistochemistry. Neuronal cytoplasmic inclusion. i. Middle frontal gyrus. Phospho-TDP-43 immunohistochemistry. Cat-eye nuclear inclusion (arrow). j. Medulla oblongata. Neurofilamentimmunohistochemistry. Numerous axonal spheroids (arrows) in the amiculum of the inferior olives. All scale bars= 10 μm pTDP-43, p62 and ubiquitin immunohistochemistry The presentation by CBS, without cerebellar ataxia, or revealed small round cytoplasmic inclusions, sometimes cerebellum lesions on imaging and pathological glial, more abundant in the superficial layers of the mid- examination (Fig. 1b, e), was clearly distinct from SCA2 dle frontal gyrus, motor cortex, and supramarginal gyrus phenotype. The neuropathology, characterized by (Fig. 1e-j). Rare pTDP-43 ‘cat eye’ intranuclear inclusions pTDP-43-positive inclusions in the neocortex, but no cere- were detected (Fig. 1i). The presence of TDP-43 positive bellar lesions or 1C2 inclusions, was also different from cytoplasmic inclusions, mainly distributed in the upper SCA2 patients (Additional file 1: Table S2). The phenotype layers of the cortex, lead to the diagnosis of type A was distinct from the late levodopa-responsive parkinson- FTLD-TDP [7]. Few cytoplasmic inclusions were found ism associated with interrupted expansions [3, 8]. Lastly, in the dentate gyrus (Fig. 1f). Scarce TDP-43 and Lewy bodies and 1C2-positive inclusions in substantia pTDP43 positive neurites were present, mainly in the nigra, pontine nuclei and cerebellum, described in few par- frontal cortex and the supramarginal gyrus (Fig. 1g-i). kinsonian patients [9], were absent in our case. This study No skein like inclusions were observed in the hypoglos- shows that ATXN2 phenotypes are not restricted to cere- sal nucleus. Ubiquitin and p62 immunohistochemistry bellar ataxia, parkinsonism and ALS, but are expanded to did not reveal inclusion in the cerebellum. No intranuc- pure isolated FTLD phenotypes. Although a coincidental lear inclusions were detected with 1C2 antibodies. No occurrence of FTLD-TDP and ATXN2 mutation cannot be alpha-synuclein immunostaining was noted in the formally excluded, all known FTLD and ALS genes were substantia nigra. Ataxin2 immunochemistry revealed normal in our patient. More importantly, an interrupted granular cytoplasmic staining in Purkinje cells of the ATXN2 expansion was previously identified in a patient cerebellum and in neurons of spinal cord, similar to that with FTD-ALS and type B FTLD-TDP pathology [10], both found in an ALS case with intermediate 32 CAG cases thus strongly support the causative genetic link expansion, and weak diffuse cytoplasmic staining in between FTLD-TDP and ATXN2. some neurons of the frontal cortex (Additional file 1: The clinical variability of ATXN2 expansions is not Figure S3). fully explained. In most repeat expansion disorders, Fournier et al. Acta Neuropathologica Communications (2018) 6:41 Page 3 of 4 somatic mosaicism of the expanded alleles contributes In summary, this case sheds new light on the signifi- to the clinical expression. Conversely to pure ATXN2 cance of ATXN2 in the spectrum of FTLD and TDP-43 expansions, no (or a low level of) brain mosaicism was pathologies and raises new challenges in the strategy observed in this case, probably because interrupted that has to be applied to reach the molecular diagnosis expansions are more stable than pure ones. Interrupted of FTLD. It enlarges the mutation spectrum of isolated expansions are also more stable than uninterrupted ones FTLD, showing that ATXN2 should be analyzed in across meiosis [3]. It possibly confers a risk of anticipa- FTLD patients, or more largely in TDP-43 cases without tion lower than in pure CAG repeats, which should be known FTLD mutations, even in absence of personal or considered in genetic counselling. Interrupted and pure familial history of cerebellar ataxia, ALS or parkinsonism. expansions may have selective topographic toxicity involving preferentially the subcortical or the neocortical Additional file structures, causing either isolated parkinsonism or Additional file 1: Supplementary methods, cohorts description, cortical syndromes. Distinct composition and/or molecular analyses and immunostaining. (DOCX 17641 kb) localization of CAAs within interrupted expansions could, in turn, be associated with different patterns of Abbreviations neurodegeneration. Finally, the phenotype might be dir- ALS: Amyotrophic Lateral Sclerosis; ATXN2: Ataxin-2; CBS: CorticoBasal ectly impacted by the modification of RNA secondary Syndrome; CT scan: Computed Tomography scan; FTLD: FrontoTemporal Lobar Degeneration; MRI: Magnetic Resonance Imaging; structure of ATXN2 transcripts including one or more PolyQ: Polyglutamine; RNA: RiboNucleic Acid; SCA2: SpinoCerebellar Ataxia CAA. CAA motif interruptions decrease the stability of type 2; SCA3: SpinoCerebellar Ataxia type 3; SCA7: SpinoCerebellar Ataxia CAG hairpin as indicated by higher ΔG in predicted type 7; SPECT: Single Photon Emission Computed Tomography; TDP-43: TAR DNA binding Protein 43; pTDP-43: Phospho-TAR DNA binding Protein 43 secondary structure (Additional file 1: Figure S2). These differences can influence the set of RNA-binding pro- Acknowledgments teins interacting with ATXN2 RNAs, and possibly inter- The authors thank the Brain Donation Program of the Brain Bank “Neuro-CEB” Brain Bank (Neuro-CEB BB-0033-00011) run by a consortium of patient associations: ARSEP fere with RNA processing, localization or translation in (association for research on multiple sclerosis), CSC (association for research on cere- specific brain structures [11]. bellar ataxias), France Parkinson, France Alzheimer and LECMA-Vaincre Alzheimer; Our patient’s peculiar phenotype could be related to and the Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain, for sample and data procurement and Dr. Ellen Gelpi (IDIBAPS Brain Bank the 27 intermediate allele, which composition is similar and Institute of Neurology, Medical University of Vienna) for helpful suggestions. that of ALS patients carrying 27 CAG alleles [12]. The Neuro-CEB Neuropathology network includes: Dr Franck Letournel (CHU An- However he did not have ALS symptoms, and we could gers), Pr Anne Vital (CHU Bordeaux), Pr Françoise Chapon (CHU Caen), Pr Catherine Godfraind (CHU Clermont-Ferrand), Pr Claude-Alain Maurage (CHU Lille), Dr Vincent not evidence selective loss of Purkinje cells in cerebellar Deramecourt (CHU Lille), Dr David Meyronnet (CHU Lyon), Dr Nathalie Streichenber- vermis [13], motor neurons alterations, nor cytoplasmic ger (CHU Lyon), Dr André Maues de Paula (CHU Marseille), Pr Valérie Rigau (CHU filamentous pTDP-43 inclusions in motor cortex and Montpellier), Dr Fanny Vandenbos-Burel (Nice), Pr Charles Duyckaerts (CHU PS Paris), Pr Danielle Seilhean (CHU PS, Paris), Dr Véronique Sazdovitch (CHU PS Paris), Dr brainstem characteristic of ALS with intermediate alleles Serge Milin (CHU Poitiers), Dr Dan Christian Chiforeanu (CHU Rennes), Pr Annie [13, 14]. As such, our patient’s phenotype is more likely Laquerrière (CHU Rouen), Dr Béatrice Lannes (CHU Strasbourg). related to the 39 repeat expansion. Availability of data and material Finally, our patient showed a rather unique lesional Brain tissues and data were provided by the Brain Bank “Neuro-CEB” Brain pattern, characterized by FTLD-TDP type A, distinct Bank (GIE Neuro-CEB BB-0033-00011) and the Neurological Tissue Bank of the both from pure or interrupted expansions and inter- Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain. mediate alleles, that expands neuropathological hall- Funding marks associated with ATXN2 expansions (Additional The research leading to these results has received funding from the program file 1: Table S3). TDP-43 inclusions were described in “Investissements d’avenir” ANR-10-IAIHU-06 (funding research facilities). This work was funded by the Programme Hospitalier de Recherche Clinique one patient carrying 42 pure ATXN2 expansion carrier (PHRC FTLD-exome, promotion AP-HP, to I.L.B, funding data collection and [15], as well as in SCA3, SCA7 and Huntington’s dis- th analyses), the 7 framework programme of the European Union (NEUROMICS, eases, three other CAG expansion disorders. Together, to AB, funding data collection and analyses). these studies and ours provide robust arguments that Authors contributions common TDP-43 related pathways can be involved, not CD, DS, CF, VS, LMP: pathologic assessments; CF, AC, VA, MB: molecular only in FTLD and ALS, but also in several CAG expan- analyses; CD, DS, VS, ST, LMP: brain bank coordination, preparation and sion disorders including interrupted ATXN2 expansion delivery of tissues; SSB, RVS: clinical evaluation of the patients; CF, VA, CD, ILB: redaction of the manuscript; AB, ML, GS: critical revisions of the disease. Based on the present study, it is difficult to manuscript; ILB, CD: supervision of the study. All authors read and approved assert how interrupted or pure expansions modify the the final manuscript. cellular localization of TDP-43 in neurons. However, it Ethics approval and consent to participate has been evidenced that ATXN2 protein ortholog associ- All tissue samples were obtained according to French and Spanish ates with TDP-43, induces its mislocalization and modi- Legislation with transfer authorization. The informed consent for post- fies its toxicity in yeast and drosophila models [4]. mortem and genetic studies were signed by the patients or by their legal Fournier et al. Acta Neuropathologica Communications (2018) 6:41 Page 4 of 4 representatives in their name, as approved by local ethics committees and 11. Sobczak K, Krzyzosiak WJ (2005) CAG repeats containing CAA interruptions allowed by Spanish and French law and by the French Ministry of Social form branched hairpin structures in spinocerebellar ataxia type 2 transcripts. Affairs and Health (AC-2013-1887, DC2015-2566, AC 2015-2576). Consent for J Biol Chem 280:3898–3910 publication of the results have been obtained. 12. Yu Z, Zhu Y, Chen-Plotkin AS, Clay-Falcone D, McCluskey L, Elman L et al (2011) PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats. PloS One 6:e17951. https://doi.org/10.1371/ Competing interests journal.pone.0017951 The authors declare that they have no competing interests 13. Tan RH, Kril JJ, McGinley C, Hassani M, Masuda-Suzukake M, Hasegawa M et al (2016) Cerebellar neuronal loss in amyotrophic lateral sclerosis cases with ATXN2 intermediate repeat expansions. Ann Neurol 79:295–305. Publisher’sNote https://doi.org/10.1002/ana.24565 Springer Nature remains neutral with regard to jurisdictional claims in 14. Hart MP, Brettschneider J, Lee VMY, Trojanowski JQ, Gitler AD (2012) Distinct published maps and institutional affiliations. TDP-43 pathology in ALS patients with ataxin 2 intermediate-length polyQ expansions. Acta Neuropathol (Berl) 124:221–230. https://doi.org/10.1007/ Author details s00401-012-0985-5 Institut du Cerveau et la Moelle épinière (ICM), Sorbonne Université, UPMC 15. Toyoshima Y, Tanaka H, Shimohata M, Kimura K, Morita T, Kakita A et al Univ Paris 06, Inserm U1127, CNRS UMR 7225, Hôpital Pitié-Salpêtrière, Paris, (2011) Spinocerebellar ataxia type 2 (SCA2) is associated with TDP-43 France. Ecole Pratique des Hautes Etudes – EPHE, PSL research University, pathology. Acta Neuropathol. (Berl.) 122:375–378. https://doi.org/10.1007/ 75014 Paris, France. Département de médecine gériatrique, Centre s00401-011-0862-7 hospitalier Rives de Seine, Courbevoie, France. Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain. Laboratoire de Neuropathologie Escourolle, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France. Department of Neurology, AP-HP - Hopital Pitié-Salpêtrière, Reference center for rare or early dementias, Institute of Memory and Alzheimer’s Disease (IM2A), Paris, France. Alzheimer disease and other Cognitive Disorders Unit, Department of Neurology, Hospital Clinic, Barcelona, Spain. Reference center for neurogenetics, Departement of Genetics, APHP, Hôpital Pitié-Salpêtrière, 75013 Paris, France. Received: 14 May 2018 Accepted: 14 May 2018 References 1. Dürr A, Smadja D, Cancel G, Lezin A, Stevanin G, Mikol J et al (1995) Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families. Brain 118(Pt 6):1573–1581 2. Koyano S, Yagishita S, Kuroiwa Y, Tanaka F, Uchihara T (2014) Neuropathological staging of spinocerebellar ataxia type 2 by semiquantitative 1C2-positive neuron typing. Nuclear translocation of cytoplasmic 1C2 underlies disease progression of spinocerebellar ataxia type 2. Brain Pathol 24:599–606. https://doi.org/10.1111/bpa.12146 3. Charles P, Camuzat A, Benammar N, Sellal F, Destée A, Bonnet A-M et al (2007) Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism? Neurology 69:1970–1975 4. Elden AC, Kim H-J, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X et al (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075. https://doi. org/10.1038/nature09320 5. Neuenschwander AG, Thai KK, Figueroa KP, Pulst SM (2014) Amyotrophic lateral sclerosis risk for spinocerebellar ataxia type 2 ATXN2 CAG repeat alleles: a meta-analysis. JAMA Neurol 71(12):1529–1534. https://doi.org/10. 1001/jamaneurol.2014.2082 6. Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, Borroni B et al (2013) Criteria for the diagnosis of corticobasal degeneration. Neurology 80:496– 503. https://doi.org/10.1212/WNL.0b013e31827f0fd1 7. Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E et al (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol (Berl) 122:111–113. https://doi.org/10.1007/ s00401-011-0845-8 8. Kim J-M, Hong S, Kim GP, Choi YJ, Kim YK, Park SS et al (2007) Importance of low-range CAG expansion and CAA interruption in SCA2 Parkinsonism. Arch Neurol 64:1510–1518 9. Takao M, Aoyama M, Ishikawa K, Sakiyama Y, Yomono H, Saito Y et al (2011) Spinocerebellar ataxia type 2 is associated with Parkinsonism and Lewy body pathology. BMJ Case Rep. 1:2011. https://doi.org/10.1136/ bcr.01.2011.3685 10. Bäumer D, East SZ, Tseu B, Zeman A, Hilton D, Talbot K et al (2014) FTLD- ALS of TDP-43 type and SCA2 in a family with a full ataxin-2 polyglutamine expansion. Acta Neuropathol (Berl) 128:597–604. https://doi.org/10.1007/ s00401-014-1277-z http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Neuropathologica Communications Springer Journals

Interrupted CAG expansions in ATXN2 gene expand the genetic spectrum of frontotemporal dementias

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Abstract

Fournier et al. Acta Neuropathologica Communications (2018) 6:41 https://doi.org/10.1186/s40478-018-0547-8 LETTER TO THE EDITOR Open Access Interrupted CAG expansions in ATXN2 gene expand the genetic spectrum of frontotemporal dementias 1† 1† 1,2 3 5 Clémence Fournier , Vincent Anquetil , Agnès Camuzat , Sandrine Stirati-Buron , Véronique Sazdovitch , 4 1,5 1,6 4,7 1 Laura Molina-Porcel , Sabrina Turbant , Daisy Rinaldi , Raquel Sánchez-Valle , Mathieu Barbier , 1,2 1,2,8 1,5 Morwena Latouche , Neuro-CEB Neuropathology Network, Giovanni Stevanin , Danielle Seilhean , 1,8 1,5 1,6* Alexis Brice , Charles Duyckaerts and Isabelle Le Ber Keywords: Frontotemporal dementia, Frontotemporal lobar degeneration, TDP-43, Ataxin 2, Amyotrophic lateral sclerosis, C9orf72, SCA2, GRN, Corticobasal degeneration, Corticobasal syndrome Spinocerebellar ataxia type 2 (SCA2) is due to a CAG carried a 39 CAG expansion interrupted by four CAA mo- repeat expansion in Ataxin-2 gene (ATXN2), encoding a tifs (CAG –CAA–CAG –CAA–CAG -CAA-CAG -CAA-- 8 4 4 9 polyglutamine (polyQ) stretch. Thirty-four or more CAG10), and a 27 CAG intermediate allele (CAG –CAA– uninterrupted (pure) CAG repeats are associated with CAG –CAA–CAG -CAA-CAG ) (Supplementary results). 4 4 8 cerebellar ataxia, slow saccades, and parkinsonism, The patient developed agrammatism, word omissions and beginning before 60 years [1]. SCA2 is associated with dysarthria, suggestive of nonfluent primary progressive neuronal loss in the cerebellum, substantia nigra, aphasia, at age 70 (Supplementary results). Brain imaging striatum and globus pallidus; and intranuclear aggrega- revealed frontal, left peri-sylvian and parietal atrophy; cere- tion of polyglutamine stretches, labelled by 1C2 bellum was normal (Fig. 1 a-d). At age 73, the association antibody, in the cerebellum [2]. When interrupted by of marked frontal executive dysfunction (planning, atten- CAA motifs, full CAG expansions produce isolated tion, inhibition, mental flexibility deficits), ideomotor levodopa-responsive parkinsonism [3]. On the other apraxia (praxis score: 4/23), akinetic-rigid parkinsonism, hand, intermediate alleles greater than 26 [4], and up to with asymmetric fronto-temporo-parietal atrophy, was con- 39 CAG repeats [5], represent a strong risk factor for sistent with a frontal-behavioral subtype of corticobasal amyotrophic lateral sclerosis (ALS) associated with neur- syndrome (CBS) [6]. He had no cerebellar syndrome. He onal TDP-43 (TAR DNA binding Protein 43) inclusions. died at age 77. No information about the patient’sfamily ATXN2 contribution to TDP-43-proteinopathies has was available. been studied mostly in ALS. We evaluated the contribu- A post-mortem examination was performed tion of ATXN2 in 31 patients with frontotemporal lobar (Supplementary methods and results). Both 39 and 27 degeneration (FTLD) and pathologically proven TDP-43 CAG alleles were found in all studied brain structures inclusions (FTLD-TDP) without known related mutation (frontal cortex, striatum, mesencephalon, occipital (Supplementary methods, Additional file 1: Table S1). cortex, cerebellum) (Additional file 1: Figure S1 and One patient (patient 5, Additional file 1: Table S1) Figure S2). Macroscopic examination revealed marked atrophy of frontal, temporal lobes, Ammon’s horn (CA1) * Correspondence: Isabelle.leber@upmc.fr and the subiculum. Neuronal loss and gliosis, associated Clémence Fournier and Vincent Anquetil contributed equally to this work. with a superficial laminar spongiosis, were severe in the Institut du Cerveau et la Moelle épinière (ICM), Sorbonne Université, UPMC superficial layers of the middle frontal gyrus, motor Univ Paris 06, Inserm U1127, CNRS UMR 7225, Hôpital Pitié-Salpêtrière, Paris, France cortex, supramarginal gyrus, CA1 and the subiculum. Department of Neurology, AP-HP - Hopital Pitié-Salpêtrière, Reference The pons (including the locus coeruleus), the cerebellum center for rare or early dementias, Institute of Memory and Alzheimer’s (Fig. 1e) and the dentate nucleus were normal. TDP-43, Disease (IM2A), Paris, France Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Fournier et al. Acta Neuropathologica Communications (2018) 6:41 Page 2 of 4 e f g h i j Fig. 1. Brain imaging and pathology. Left: Brain MRI and CT scan and HMPAO-SPECT examination of patient 5 (aged 73 years). a.Brain T1 axial sections showing marked bilateral frontal atrophy, associated with predominantly left parietal atrophy (arrows). b. T1 axial and coronal sections, showing no cerebellar atrophy. c. brain CT scan (axial sections) showing predominantly left peri-sylvian and frontal atrophy (arrows). d. HMPAO-SPECT examination (axial and coronal sections) showing bilateral, predominantly left (arrow), hypoperfusion. L: left; R: right. Right: Brain pathological lesions of patient 5. e. Cerebellum. Haematoxylin-Eosin stain. Normal density of Purkinje cells, of granule cells and of glomeruli. f. Dentate gyrus. Phospho-TDP-43 immunohistochemistry. Neuronal cytoplasmic inclusion. g. Upper layers of the middle frontal gyrus. Phospho-TDP-43 immunohistochemistry. Several cytoplasmic inclusions (short arrows) in glial cells. One phospho-TDP-43 positive neurite (long arrow). h. Middle frontal gyrus. Phospho-TDP-43immunohistochemistry. Neuronal cytoplasmic inclusion. i. Middle frontal gyrus. Phospho-TDP-43 immunohistochemistry. Cat-eye nuclear inclusion (arrow). j. Medulla oblongata. Neurofilamentimmunohistochemistry. Numerous axonal spheroids (arrows) in the amiculum of the inferior olives. All scale bars= 10 μm pTDP-43, p62 and ubiquitin immunohistochemistry The presentation by CBS, without cerebellar ataxia, or revealed small round cytoplasmic inclusions, sometimes cerebellum lesions on imaging and pathological glial, more abundant in the superficial layers of the mid- examination (Fig. 1b, e), was clearly distinct from SCA2 dle frontal gyrus, motor cortex, and supramarginal gyrus phenotype. The neuropathology, characterized by (Fig. 1e-j). Rare pTDP-43 ‘cat eye’ intranuclear inclusions pTDP-43-positive inclusions in the neocortex, but no cere- were detected (Fig. 1i). The presence of TDP-43 positive bellar lesions or 1C2 inclusions, was also different from cytoplasmic inclusions, mainly distributed in the upper SCA2 patients (Additional file 1: Table S2). The phenotype layers of the cortex, lead to the diagnosis of type A was distinct from the late levodopa-responsive parkinson- FTLD-TDP [7]. Few cytoplasmic inclusions were found ism associated with interrupted expansions [3, 8]. Lastly, in the dentate gyrus (Fig. 1f). Scarce TDP-43 and Lewy bodies and 1C2-positive inclusions in substantia pTDP43 positive neurites were present, mainly in the nigra, pontine nuclei and cerebellum, described in few par- frontal cortex and the supramarginal gyrus (Fig. 1g-i). kinsonian patients [9], were absent in our case. This study No skein like inclusions were observed in the hypoglos- shows that ATXN2 phenotypes are not restricted to cere- sal nucleus. Ubiquitin and p62 immunohistochemistry bellar ataxia, parkinsonism and ALS, but are expanded to did not reveal inclusion in the cerebellum. No intranuc- pure isolated FTLD phenotypes. Although a coincidental lear inclusions were detected with 1C2 antibodies. No occurrence of FTLD-TDP and ATXN2 mutation cannot be alpha-synuclein immunostaining was noted in the formally excluded, all known FTLD and ALS genes were substantia nigra. Ataxin2 immunochemistry revealed normal in our patient. More importantly, an interrupted granular cytoplasmic staining in Purkinje cells of the ATXN2 expansion was previously identified in a patient cerebellum and in neurons of spinal cord, similar to that with FTD-ALS and type B FTLD-TDP pathology [10], both found in an ALS case with intermediate 32 CAG cases thus strongly support the causative genetic link expansion, and weak diffuse cytoplasmic staining in between FTLD-TDP and ATXN2. some neurons of the frontal cortex (Additional file 1: The clinical variability of ATXN2 expansions is not Figure S3). fully explained. In most repeat expansion disorders, Fournier et al. Acta Neuropathologica Communications (2018) 6:41 Page 3 of 4 somatic mosaicism of the expanded alleles contributes In summary, this case sheds new light on the signifi- to the clinical expression. Conversely to pure ATXN2 cance of ATXN2 in the spectrum of FTLD and TDP-43 expansions, no (or a low level of) brain mosaicism was pathologies and raises new challenges in the strategy observed in this case, probably because interrupted that has to be applied to reach the molecular diagnosis expansions are more stable than pure ones. Interrupted of FTLD. It enlarges the mutation spectrum of isolated expansions are also more stable than uninterrupted ones FTLD, showing that ATXN2 should be analyzed in across meiosis [3]. It possibly confers a risk of anticipa- FTLD patients, or more largely in TDP-43 cases without tion lower than in pure CAG repeats, which should be known FTLD mutations, even in absence of personal or considered in genetic counselling. Interrupted and pure familial history of cerebellar ataxia, ALS or parkinsonism. expansions may have selective topographic toxicity involving preferentially the subcortical or the neocortical Additional file structures, causing either isolated parkinsonism or Additional file 1: Supplementary methods, cohorts description, cortical syndromes. Distinct composition and/or molecular analyses and immunostaining. (DOCX 17641 kb) localization of CAAs within interrupted expansions could, in turn, be associated with different patterns of Abbreviations neurodegeneration. Finally, the phenotype might be dir- ALS: Amyotrophic Lateral Sclerosis; ATXN2: Ataxin-2; CBS: CorticoBasal ectly impacted by the modification of RNA secondary Syndrome; CT scan: Computed Tomography scan; FTLD: FrontoTemporal Lobar Degeneration; MRI: Magnetic Resonance Imaging; structure of ATXN2 transcripts including one or more PolyQ: Polyglutamine; RNA: RiboNucleic Acid; SCA2: SpinoCerebellar Ataxia CAA. CAA motif interruptions decrease the stability of type 2; SCA3: SpinoCerebellar Ataxia type 3; SCA7: SpinoCerebellar Ataxia CAG hairpin as indicated by higher ΔG in predicted type 7; SPECT: Single Photon Emission Computed Tomography; TDP-43: TAR DNA binding Protein 43; pTDP-43: Phospho-TAR DNA binding Protein 43 secondary structure (Additional file 1: Figure S2). These differences can influence the set of RNA-binding pro- Acknowledgments teins interacting with ATXN2 RNAs, and possibly inter- The authors thank the Brain Donation Program of the Brain Bank “Neuro-CEB” Brain Bank (Neuro-CEB BB-0033-00011) run by a consortium of patient associations: ARSEP fere with RNA processing, localization or translation in (association for research on multiple sclerosis), CSC (association for research on cere- specific brain structures [11]. bellar ataxias), France Parkinson, France Alzheimer and LECMA-Vaincre Alzheimer; Our patient’s peculiar phenotype could be related to and the Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain, for sample and data procurement and Dr. Ellen Gelpi (IDIBAPS Brain Bank the 27 intermediate allele, which composition is similar and Institute of Neurology, Medical University of Vienna) for helpful suggestions. that of ALS patients carrying 27 CAG alleles [12]. The Neuro-CEB Neuropathology network includes: Dr Franck Letournel (CHU An- However he did not have ALS symptoms, and we could gers), Pr Anne Vital (CHU Bordeaux), Pr Françoise Chapon (CHU Caen), Pr Catherine Godfraind (CHU Clermont-Ferrand), Pr Claude-Alain Maurage (CHU Lille), Dr Vincent not evidence selective loss of Purkinje cells in cerebellar Deramecourt (CHU Lille), Dr David Meyronnet (CHU Lyon), Dr Nathalie Streichenber- vermis [13], motor neurons alterations, nor cytoplasmic ger (CHU Lyon), Dr André Maues de Paula (CHU Marseille), Pr Valérie Rigau (CHU filamentous pTDP-43 inclusions in motor cortex and Montpellier), Dr Fanny Vandenbos-Burel (Nice), Pr Charles Duyckaerts (CHU PS Paris), Pr Danielle Seilhean (CHU PS, Paris), Dr Véronique Sazdovitch (CHU PS Paris), Dr brainstem characteristic of ALS with intermediate alleles Serge Milin (CHU Poitiers), Dr Dan Christian Chiforeanu (CHU Rennes), Pr Annie [13, 14]. As such, our patient’s phenotype is more likely Laquerrière (CHU Rouen), Dr Béatrice Lannes (CHU Strasbourg). related to the 39 repeat expansion. Availability of data and material Finally, our patient showed a rather unique lesional Brain tissues and data were provided by the Brain Bank “Neuro-CEB” Brain pattern, characterized by FTLD-TDP type A, distinct Bank (GIE Neuro-CEB BB-0033-00011) and the Neurological Tissue Bank of the both from pure or interrupted expansions and inter- Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain. mediate alleles, that expands neuropathological hall- Funding marks associated with ATXN2 expansions (Additional The research leading to these results has received funding from the program file 1: Table S3). TDP-43 inclusions were described in “Investissements d’avenir” ANR-10-IAIHU-06 (funding research facilities). This work was funded by the Programme Hospitalier de Recherche Clinique one patient carrying 42 pure ATXN2 expansion carrier (PHRC FTLD-exome, promotion AP-HP, to I.L.B, funding data collection and [15], as well as in SCA3, SCA7 and Huntington’s dis- th analyses), the 7 framework programme of the European Union (NEUROMICS, eases, three other CAG expansion disorders. Together, to AB, funding data collection and analyses). these studies and ours provide robust arguments that Authors contributions common TDP-43 related pathways can be involved, not CD, DS, CF, VS, LMP: pathologic assessments; CF, AC, VA, MB: molecular only in FTLD and ALS, but also in several CAG expan- analyses; CD, DS, VS, ST, LMP: brain bank coordination, preparation and sion disorders including interrupted ATXN2 expansion delivery of tissues; SSB, RVS: clinical evaluation of the patients; CF, VA, CD, ILB: redaction of the manuscript; AB, ML, GS: critical revisions of the disease. Based on the present study, it is difficult to manuscript; ILB, CD: supervision of the study. All authors read and approved assert how interrupted or pure expansions modify the the final manuscript. cellular localization of TDP-43 in neurons. However, it Ethics approval and consent to participate has been evidenced that ATXN2 protein ortholog associ- All tissue samples were obtained according to French and Spanish ates with TDP-43, induces its mislocalization and modi- Legislation with transfer authorization. The informed consent for post- fies its toxicity in yeast and drosophila models [4]. mortem and genetic studies were signed by the patients or by their legal Fournier et al. Acta Neuropathologica Communications (2018) 6:41 Page 4 of 4 representatives in their name, as approved by local ethics committees and 11. Sobczak K, Krzyzosiak WJ (2005) CAG repeats containing CAA interruptions allowed by Spanish and French law and by the French Ministry of Social form branched hairpin structures in spinocerebellar ataxia type 2 transcripts. Affairs and Health (AC-2013-1887, DC2015-2566, AC 2015-2576). Consent for J Biol Chem 280:3898–3910 publication of the results have been obtained. 12. Yu Z, Zhu Y, Chen-Plotkin AS, Clay-Falcone D, McCluskey L, Elman L et al (2011) PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats. PloS One 6:e17951. https://doi.org/10.1371/ Competing interests journal.pone.0017951 The authors declare that they have no competing interests 13. Tan RH, Kril JJ, McGinley C, Hassani M, Masuda-Suzukake M, Hasegawa M et al (2016) Cerebellar neuronal loss in amyotrophic lateral sclerosis cases with ATXN2 intermediate repeat expansions. Ann Neurol 79:295–305. Publisher’sNote https://doi.org/10.1002/ana.24565 Springer Nature remains neutral with regard to jurisdictional claims in 14. Hart MP, Brettschneider J, Lee VMY, Trojanowski JQ, Gitler AD (2012) Distinct published maps and institutional affiliations. TDP-43 pathology in ALS patients with ataxin 2 intermediate-length polyQ expansions. Acta Neuropathol (Berl) 124:221–230. https://doi.org/10.1007/ Author details s00401-012-0985-5 Institut du Cerveau et la Moelle épinière (ICM), Sorbonne Université, UPMC 15. Toyoshima Y, Tanaka H, Shimohata M, Kimura K, Morita T, Kakita A et al Univ Paris 06, Inserm U1127, CNRS UMR 7225, Hôpital Pitié-Salpêtrière, Paris, (2011) Spinocerebellar ataxia type 2 (SCA2) is associated with TDP-43 France. Ecole Pratique des Hautes Etudes – EPHE, PSL research University, pathology. Acta Neuropathol. (Berl.) 122:375–378. https://doi.org/10.1007/ 75014 Paris, France. Département de médecine gériatrique, Centre s00401-011-0862-7 hospitalier Rives de Seine, Courbevoie, France. Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain. Laboratoire de Neuropathologie Escourolle, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France. Department of Neurology, AP-HP - Hopital Pitié-Salpêtrière, Reference center for rare or early dementias, Institute of Memory and Alzheimer’s Disease (IM2A), Paris, France. Alzheimer disease and other Cognitive Disorders Unit, Department of Neurology, Hospital Clinic, Barcelona, Spain. Reference center for neurogenetics, Departement of Genetics, APHP, Hôpital Pitié-Salpêtrière, 75013 Paris, France. Received: 14 May 2018 Accepted: 14 May 2018 References 1. Dürr A, Smadja D, Cancel G, Lezin A, Stevanin G, Mikol J et al (1995) Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families. 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Published: May 30, 2018

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