Advertisement

Acta Neuropathologica

, Volume 128, Issue 5, pp 705–722 | Cite as

The autophagy/lysosome pathway is impaired in SCA7 patients and SCA7 knock-in mice

  • Sandro AlvesEmail author
  • Florence Cormier-Dequaire
  • Martina Marinello
  • Thibaut Marais
  • Marie-Paule Muriel
  • Florian Beaumatin
  • Fanny Charbonnier-Beaupel
  • Khadija Tahiri
  • Danielle Seilhean
  • Khalid El Hachimi
  • Merle Ruberg
  • Giovanni Stevanin
  • Martine Barkats
  • Wilfred den Dunnen
  • Muriel Priault
  • Alexis Brice
  • Alexandra Durr
  • Jean-Christophe Corvol
  • Annie SittlerEmail author
Original Paper

Abstract

There is still no treatment for polyglutamine disorders, but clearance of mutant proteins might represent a potential therapeutic strategy. Autophagy, the major pathway for organelle and protein turnover, has been implicated in these diseases. To determine whether the autophagy/lysosome system contributes to the pathogenesis of spinocerebellar ataxia type 7 (SCA7), caused by expansion of a polyglutamine tract in the ataxin-7 protein, we looked for biochemical, histological and transcriptomic abnormalities in components of the autophagy/lysosome pathway in a knock-in mouse model of the disease, postmortem brain and peripheral blood mononuclear cells (PBMC) from patients. In the mouse model, mutant ataxin-7 accumulated in inclusions immunoreactive for the autophagy-associated proteins mTOR, beclin-1, p62 and ubiquitin. Atypical accumulations of the autophagosome/lysosome markers LC3, LAMP-1, LAMP2 and cathepsin-D were also found in the cerebellum of the SCA7 knock-in mice. In patients, abnormal accumulations of autophagy markers were detected in the cerebellum and cerebral cortex of patients, but not in the striatum that is spared in SCA7, suggesting that autophagy might be impaired by the selective accumulation of mutant ataxin-7. In vitro studies demonstrated that the autophagic flux was impaired in cells overexpressing full-length mutant ataxin-7. Interestingly, the expression of the early autophagy-associated gene ATG12 was increased in PBMC from SCA7 patients in correlation with disease severity. These results provide evidence that the autophagy/lysosome pathway is impaired in neurons undergoing degeneration in SCA7. Autophagy/lysosome-associated molecules might, therefore, be useful markers for monitoring the effects of potential therapeutic approaches using modulators of autophagy in SCA7 and other autophagy/lysosome-associated neurodegenerative disorders.

Keywords

Ataxia Autophagy Lysosome SCA7 knock-in mouse Patients Transcriptome 

Abbreviations

SCA7

Spinocerebellar ataxia type 7

polyQ

Polyglutamine

ATXN7

Ataxin-7

KI

Knock-in

PBMC

Peripheral blood mononuclear cells

PC

Purkinje cell

ATG

Autophagy-related protein

LC3

Microtubule-associated protein 1 light chain (MAP1) light chain 3

Lamp-1

Lysosomal-associated membrane protein 1

Lamp-2

Lysosomal associated membrane protein 2

PML

Promyelocytic leukemia protein

APP

Amyloid precursor protein

Notes

Acknowledgments

This study was supported by grants from the French National Research Agency (ANR-07-MRAR-025-01 to A.S), the French Association against Myopathies (AFM, to AB and long-term fellowship to SA), the French association Connaitre les Syndrômes Cérébelleux (short-term fellowship to SA), and the French Foundation for Medical Research (FRM, to JCC and FC-D), as well as the “Investissements d’avenir” program ANR-10-IAIHU-06 (to the Brain and Spine Institute, Paris). We thank Prof. H. Zoghbi (Baylor College of Medicine, Houston, Texas, USA) for the SCA7 KI mice. We are grateful to Pr. C. Duyckaerts for brain samples and Drs. C. Marelli and C. Jauffret for blood samples from SCA7 patients. We would also like to thank the Cellular Imaging Platform of the Pitié Salpêtrière, especially Dr. A. Dauphin, for advice on confocal imaging, and J. Garrigue and W. Carpentier for technical assistance. The authors have no additional financial interests.

Supplementary material

401_2014_1289_MOESM1_ESM.pdf (126 kb)
Supplementary material 1 (PDF 126 kb)
401_2014_1289_MOESM2_ESM.pdf (10.2 mb)
Supplementary material 2 (PDF 10,416 kb)
401_2014_1289_MOESM3_ESM.pdf (119 kb)
Supplementary material 3 (PDF 120 kb)

References

  1. 1.
    Benton CS, de Silva R, Rutledge SL, Bohlega S, Ashizawa T, Zoghbi HY (1998) Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype. Neurology 51:1081–1086PubMedCrossRefGoogle Scholar
  2. 2.
    Cancel G, Duyckaerts C, Holmberg M, Zander C, Yvert G, Lebre AS, Ruberg M et al (2000) Distribution of ataxin-7 in normal human brain and retina. Brain 123(Pt 12):2519–2530PubMedCrossRefGoogle Scholar
  3. 3.
    Chort A, Alves S, Marinello M, Dufresnois B, Dornbierer JG, Tesson C, Latouche M et al (2013) Interferon beta induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice. Brain 136:1732–1745. doi: 10.1093/brain/awt061 PubMedCrossRefGoogle Scholar
  4. 4.
    Chou AH, Chen CY, Chen SY, Chen WJ, Chen YL, Weng YS, Wang HL (2010) Polyglutamine-expanded ataxin-7 causes cerebellar dysfunction by inducing transcriptional dysregulation. Neurochem Int 56:329–339. doi: 10.1016/j.neuint.2009.11.003 PubMedCrossRefGoogle Scholar
  5. 5.
    Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E, Hansen L et al (2010) Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS ONE 5:e9313. doi: 10.1371/journal.pone.0009313 PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Cuervo AM, Wong E (2014) Chaperone-mediated autophagy: roles in disease and aging. Cell Res 24:92–104. doi: 10.1038/cr.2013.153 PubMedCrossRefGoogle Scholar
  7. 7.
    David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, Weber C et al (1997) Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 17:65–70PubMedCrossRefGoogle Scholar
  8. 8.
    Eskelinen EL (2006) Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol Aspects Med 27:495–502. doi: 10.1016/j.mam.2006.08.005 PubMedCrossRefGoogle Scholar
  9. 9.
    Gusella JF, MacDonald ME (2000) Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nat Rev Neurosci 1:109–115PubMedCrossRefGoogle Scholar
  10. 10.
    Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889. doi: 10.1038/nature04724 PubMedCrossRefGoogle Scholar
  11. 11.
    He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93. doi: 10.1146/annurev-genet-102808-114910 PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Helmlinger D, Hardy S, Sasorith S, Klein F, Robert F, Weber C, Miguet L et al (2004) Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum Mol Genet 13:1257–1265PubMedCrossRefGoogle Scholar
  13. 13.
    Heng MY, Duong DK, Albin RL, Tallaksen-Greene SJ, Hunter JM, Lesort MJ, Osmand A et al (2010) Early autophagic response in a novel knock-in model of Huntington disease. Hum Mol Genet 19:3702–3720. doi: 10.1093/hmg/ddq285 PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Holmberg M, Duyckaerts C, Durr A, Cancel G, Gourfinkel-An I, Damier P, Faucheux B et al (1998) Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet 7:913–918PubMedCrossRefGoogle Scholar
  15. 15.
    Ichimura Y, Komatsu M (2010) Selective degradation of p62 by autophagy. Semin Immunopathol 32:431–436. doi: 10.1007/s00281-010-0220-1 PubMedCrossRefGoogle Scholar
  16. 16.
    Ichimura Y, Kumanomidou T, Sou YS, Mizushima T, Ezaki J, Ueno T, Kominami E et al (2008) Structural basis for sorting mechanism of p62 in selective autophagy. J Biol Chem 283:22847–22857. doi: 10.1074/jbc.M802182200 PubMedCrossRefGoogle Scholar
  17. 17.
    Janer A, Martin E, Muriel MP, Latouche M, Fujigasaki H, Ruberg M, Brice A et al (2006) PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins. J Cell Biol 174:65–76PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E et al (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19:5720–5728. doi: 10.1093/emboj/19.21.5720 PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Kegel KB, Kim M, Sapp E, McIntyre C, Castano JG, Aronin N, DiFiglia M (2000) Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J Neurosci 20:7268–7278PubMedGoogle Scholar
  20. 20.
    Klionsky DJ, Codogno P, Cuervo AM, Deretic V, Elazar Z, Fueyo-Margareto J, Gewirtz DA et al (2010) A comprehensive glossary of autophagy-related molecules and processes. Autophagy 6:438–448. doi: 10.4161/auto.6.4.12244 PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477 pii: S1534580704000991PubMedCrossRefGoogle Scholar
  22. 22.
    Ma JF, Huang Y, Chen SD, Halliday G (2010) Immunohistochemical evidence for macroautophagy in neurones and endothelial cells in Alzheimer’s disease. Neuropathol Appl Neurobiol 36:312–319. doi: 10.1111/j.1365-2990.2010.01067.x PubMedCrossRefGoogle Scholar
  23. 23.
    Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S, de Vries R et al (2010) Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci 13:567–576. doi: 10.1038/nn.2528 PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Michalik A, Martin JJ, Van Broeckhoven C (2004) Spinocerebellar ataxia type 7 associated with pigmentary retinal dystrophy. Eur J Hum Genet 12:2–15. doi: 10.1038/sj.ejhg.52011085201108 PubMedCrossRefGoogle Scholar
  25. 25.
    Mizushima N (2010) The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 22:132–139. doi: 10.1016/j.ceb.2009.12.004 PubMedCrossRefGoogle Scholar
  26. 26.
    Mizushima N, Noda T, Ohsumi Y (1999) Apg16p is required for the function of the Apg12p-Apg5p conjugate in the yeast autophagy pathway. EMBO J 18:3888–3896. doi: 10.1093/emboj/18.14.3888 PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Mookerjee S, Papanikolaou T, Guyenet SJ, Sampath V, Lin A, Vitelli C, DeGiacomo F et al (2009) Posttranslational modification of ataxin-7 at lysine 257 prevents autophagy-mediated turnover of an N-terminal caspase-7 cleavage fragment. J Neurosci 29:15134–15144. doi: 10.1523/JNEUROSCI.4720-09.2009 PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Nakamura Y, Tagawa K, Oka T, Sasabe T, Ito H, Shiwaku H, La Spada AR et al (2012) Ataxin-7 associates with microtubules and stabilizes the cytoskeletal network. Hum Mol Genet 21:1099–1110. doi: 10.1093/hmg/ddr539 PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Nascimento-Ferreira I, Nobrega C, Vasconcelos-Ferreira A, Onofre I, Albuquerque D, Aveleira C, Hirai H et al (2013) Beclin 1 mitigates motor and neuropathological deficits in genetic mouse models of Machado-Joseph disease. Brain 136:2173–2188. doi: 10.1093/brain/awt144 PubMedCrossRefGoogle Scholar
  30. 30.
    Nascimento-Ferreira I, Santos-Ferreira T, Sousa-Ferreira L, Auregan G, Onofre I, Alves S, Dufour N et al (2011) Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado-Joseph disease. Brain 134:1400–1415. doi: 10.1093/brain/awr047 PubMedCrossRefGoogle Scholar
  31. 31.
    Palhan VB, Chen S, Peng GH, Tjernberg A, Gamper AM, Fan Y, Chait BT et al (2005) Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc Natl Acad Sci USA 102:8472–8477PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A et al (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282:24131–24145. doi: 10.1074/jbc.M702824200 PubMedCrossRefGoogle Scholar
  33. 33.
    Pankiv S, Lamark T, Bruun JA, Overvatn A, Bjorkoy G, Johansen T (2010) Nucleocytoplasmic shuttling of p62/SQSTM1 and its role in recruitment of nuclear polyubiquitinated proteins to promyelocytic leukemia bodies. J Biol Chem 285:5941–5953. doi: 10.1074/jbc.M109.039925 PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S et al (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 118:2190–2199. doi: 10.1172/JCI33585 PubMedPubMedCentralGoogle Scholar
  35. 35.
    Ramachandran N, Munteanu I, Wang P, Ruggieri A, Rilstone JJ, Israelian N, Naranian T et al (2013) VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy. Acta Neuropathol 125:439–457. doi: 10.1007/s00401-012-1073-6 PubMedCrossRefGoogle Scholar
  36. 36.
    Ravikumar B, Acevedo-Arozena A, Imarisio S, Berger Z, Vacher C, O’Kane CJ, Brown SD et al (2005) Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat Genet 37:771–776. doi: 10.1038/ng1591 PubMedCrossRefGoogle Scholar
  37. 37.
    Ravikumar B, Duden R, Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11:1107–1117PubMedCrossRefGoogle Scholar
  38. 38.
    Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F et al (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–595. doi: 10.1038/ng1362ng1362 PubMedCrossRefGoogle Scholar
  39. 39.
    Rosenfeldt MT, Nixon C, Liu E, Mah LY, Ryan KM (2012) Analysis of macroautophagy by immunohistochemistry. Autophagy 8:963–969. doi: 10.4161/auto.20186 PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Rub U, Schols L, Paulson H, Auburger G, Kermer P, Jen JC, Seidel K et al (2013) Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7. Prog Neurobiol 104:38–66. doi: 10.1016/j.pneurobio.2013.01.001 PubMedCrossRefGoogle Scholar
  41. 41.
    Sarkar S, Krishna G, Imarisio S, Saiki S, O’Kane CJ, Rubinsztein DC (2008) A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum Mol Genet 17:170–178. doi: 10.1093/hmg/ddm294 PubMedCrossRefGoogle Scholar
  42. 42.
    Sarkar S, Perlstein EO, Imarisio S, Pineau S, Cordenier A, Maglathlin RL, Webster JA et al (2007) Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat Chem Biol 3:331–338. doi: 10.1038/nchembio883 PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Seidel K, Siswanto S, Brunt ER, den Dunnen W, Korf HW, Rub U (2012) Brain pathology of spinocerebellar ataxias. Acta Neuropathol 124:1–21. doi: 10.1007/s00401-012-1000-x PubMedCrossRefGoogle Scholar
  44. 44.
    Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T, MacDonald M et al (2006) Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J Biol Chem 281:14474–14485. doi: 10.1074/jbc.M600364200 PubMedCrossRefGoogle Scholar
  45. 45.
    Shvets E, Fass E, Scherz-Shouval R, Elazar Z (2008) The N-terminus and Phe52 residue of LC3 recruit p62/SQSTM1 into autophagosomes. J Cell Sci 121:2685–2695. doi: 10.1242/jcs.026005 PubMedCrossRefGoogle Scholar
  46. 46.
    Sittler A, Walter S, Wedemeyer N, Hasenbank R, Scherzinger E, Eickhoff H, Bates GP et al (1998) SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. Mol Cell 2:427–436PubMedCrossRefGoogle Scholar
  47. 47.
    Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A et al (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci 29:13578–13588. doi: 10.1523/JNEUROSCI.4390-09.2009 PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A et al (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS ONE 5:e9979. doi: 10.1371/journal.pone.0009979 PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Stevanin G, Durr A, Brice A (2000) Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology. Eur J Hum Genet 8:4–18. doi: 10.1038/sj.ejhg.5200403 PubMedCrossRefGoogle Scholar
  50. 50.
    Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R et al (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307:1282–1288. doi: 10.1126/science.1105681 PubMedCrossRefGoogle Scholar
  51. 51.
    Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa M et al (2004) Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10:148–154PubMedCrossRefGoogle Scholar
  52. 52.
    van de Warrenburg BP, Notermans NC, Schelhaas HJ, van Alfen N, Sinke RJ, Knoers NV, Zwarts MJ et al (2004) Peripheral nerve involvement in spinocerebellar ataxias. Arch Neurol 61:257–261. doi: 10.1001/archneur.61.2.25761/2/257 PubMedCrossRefGoogle Scholar
  53. 53.
    Wong E, Cuervo AM (2010) Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 13:805–811. doi: 10.1038/nn.2575 PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Wong E, Cuervo AM (2010) Integration of clearance mechanisms: the proteasome and autophagy. Cold Spring Harb Perspect Biol 2:a006734. doi: 10.1101/cshperspect.a006734 PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Wu G, Wang X, Feng X, Zhang A, Li J, Gu K, Huang J et al (2011) Altered expression of autophagic genes in the peripheral leukocytes of patients with sporadic Parkinson’s disease. Brain Res 1394:105–111. doi: 10.1016/j.brainres.2011.04.013 PubMedCrossRefGoogle Scholar
  56. 56.
    Yoo SY, Pennesi ME, Weeber EJ, Xu B, Atkinson R, Chen S, Armstrong DL et al (2003) SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron 37:383–401PubMedCrossRefGoogle Scholar
  57. 57.
    Yu X, Ajayi A, Boga NR, Strom AL (2012) Differential degradation of full-length and cleaved ataxin-7 fragments in a novel stable inducible SCA7 model. J Mol Neurosci 47:219–233. doi: 10.1007/s12031-012-9722-8 PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Yue Z, Holstein GR, Chait BT, Wang QJ (2009) Using genetic mouse models to study the biology and pathology of autophagy in the central nervous system. Methods Enzymol 453:159–180. doi: 10.1016/S0076-6879(08)04008-1 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Sandro Alves
    • 1
    • 2
    • 3
    • 13
    Email author
  • Florence Cormier-Dequaire
    • 1
    • 2
    • 3
    • 4
    • 13
  • Martina Marinello
    • 1
    • 2
    • 3
    • 13
  • Thibaut Marais
    • 5
    • 6
  • Marie-Paule Muriel
    • 1
    • 2
    • 3
    • 13
  • Florian Beaumatin
    • 7
    • 8
  • Fanny Charbonnier-Beaupel
    • 1
    • 2
    • 3
    • 4
    • 13
  • Khadija Tahiri
    • 1
    • 2
    • 3
    • 4
    • 13
  • Danielle Seilhean
    • 9
  • Khalid El Hachimi
    • 1
    • 2
    • 3
    • 11
    • 13
  • Merle Ruberg
    • 1
    • 2
    • 3
    • 13
  • Giovanni Stevanin
    • 1
    • 2
    • 3
    • 11
    • 12
    • 13
  • Martine Barkats
    • 5
    • 6
  • Wilfred den Dunnen
    • 10
  • Muriel Priault
    • 7
    • 8
  • Alexis Brice
    • 1
    • 2
    • 3
    • 12
    • 13
  • Alexandra Durr
    • 1
    • 2
    • 3
    • 12
    • 13
  • Jean-Christophe Corvol
    • 1
    • 2
    • 3
    • 4
    • 13
  • Annie Sittler
    • 1
    • 2
    • 3
    • 13
    Email author
  1. 1.Sorbonne Universités, UPMC Univ. Paris 6, ICMParisFrance
  2. 2.Institut National de la Santé et de la Recherche Médicale, U1127, ICMParisFrance
  3. 3.Centre National pour la Recherche Scientifique, UMR 7225, ICMParisFrance
  4. 4.Centre d’Investigation Clinique (CIC-9503), Hôpital de la Pitié-SalpêtrièreParisFrance
  5. 5.Institut National de la Santé et de la Recherche Médicale U974ParisFrance
  6. 6.UPMC-AIM UMR S974, CNRS UMR 7215, Institut de MyologieParisFrance
  7. 7.CNRS, Institut de Biochimie et de Génétique Cellulaire, UMR5095BordeauxFrance
  8. 8.Université de Bordeaux, Institut de Biochimie et de Génétique Cellulaire, UMR5095BordeauxFrance
  9. 9.Laboratoire de Neuropathologie Escourolle-Hôpital de la Pitié Salpêtrière, AP-HPParisFrance
  10. 10.Department of Pathology and Medical BiologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
  11. 11.Laboratoire de NeurogénétiqueEcole Pratique des Hautes Etudes, ICM, Hôpital de la Pitié-SalpêtrièreParisFrance
  12. 12.Département de Génétique et CytogénétiqueAP-HP, G-H Pitié-SalpêtrièreParisFrance
  13. 13.ICM, Hôpital de la Pitié-SalpêtrièreParisFrance

Personalised recommendations