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

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• 作者：Sandro Alves (1) (13) (2) (3)
  Florence Cormier-Dequaire (1) (13) (2) (3) (4)
  Martina Marinello (1) (13) (2) (3)
  Thibaut Marais (5) (6)
  Marie-Paule Muriel (1) (13) (2) (3)
  Florian Beaumatin (7) (8)
  Fanny Charbonnier-Beaupel (1) (13) (2) (3) (4)
  Khadija Tahiri (1) (13) (2) (3) (4)
  Danielle Seilhean (9)
  Khalid El Hachimi (1) (11) (13) (2) (3)
  Merle Ruberg (1) (13) (2) (3)
  Giovanni Stevanin (1) (11) (12) (13) (2) (3)
  Martine Barkats (5) (6)
  Wilfred den Dunnen (10)
  Muriel Priault (7) (8)
  Alexis Brice (1) (12) (13) (2) (3)
  Alexandra Durr (1) (12) (13) (2) (3)
  Jean-Christophe Corvol (1) (13) (2) (3) (4)
  Annie Sittler (1) (13) (2) (3)
  
• 关键词：Ataxia ; Autophagy ; Lysosome ; SCA7 knock ; in mouse ; Patients ; Transcriptome
• 刊名：Acta Neuropathologica
• 出版年：2014
• 出版时间：November 2014
• 年：2014
• 卷：128
• 期：5
• 页码：705-722
• 全文大小：6,037 KB
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• 作者单位：Sandro Alves (1) (13) (2) (3)
  Florence Cormier-Dequaire (1) (13) (2) (3) (4)
  Martina Marinello (1) (13) (2) (3)
  Thibaut Marais (5) (6)
  Marie-Paule Muriel (1) (13) (2) (3)
  Florian Beaumatin (7) (8)
  Fanny Charbonnier-Beaupel (1) (13) (2) (3) (4)
  Khadija Tahiri (1) (13) (2) (3) (4)
  Danielle Seilhean (9)
  Khalid El Hachimi (1) (11) (13) (2) (3)
  Merle Ruberg (1) (13) (2) (3)
  Giovanni Stevanin (1) (11) (12) (13) (2) (3)
  Martine Barkats (5) (6)
  Wilfred den Dunnen (10)
  Muriel Priault (7) (8)
  Alexis Brice (1) (12) (13) (2) (3)
  Alexandra Durr (1) (12) (13) (2) (3)
  Jean-Christophe Corvol (1) (13) (2) (3) (4)
  Annie Sittler (1) (13) (2) (3)
  
  1. Sorbonne Universit茅s, UPMC Univ. Paris 6, ICM, 75013, Paris, France
  13. ICM, H么pital de la Piti茅-Salp锚tri猫re, 47 Bd de l鈥橦么pital, 75013, Paris, France
  2. Institut National de la Sant茅 et de la Recherche M茅dicale, U1127, ICM, 75013, Paris, France
  3. Centre National pour la Recherche Scientifique, UMR 7225, ICM, 75013, Paris, France
  4. Centre d鈥橧nvestigation Clinique (CIC-9503), H么pital de la Piti茅-Salp锚tri猫re, 75013, Paris, France
  5. Institut National de la Sant茅 et de la Recherche M茅dicale U974, 75013, Paris, France
  6. UPMC-AIM UMR S974, CNRS UMR 7215, Institut de Myologie, 75013, Paris, France
  7. CNRS, Institut de Biochimie et de G茅n茅tique Cellulaire, UMR5095, 33000, Bordeaux, France
  8. Universit茅 de Bordeaux, Institut de Biochimie et de G茅n茅tique Cellulaire, UMR5095, 33000, Bordeaux, France
  9. Laboratoire de Neuropathologie Escourolle-H么pital de la Piti茅 Salp锚tri猫re, AP-HP, 47 Bd de, l鈥橦么pital, 75013, Paris, France
  11. Laboratoire de Neurog茅n茅tique, Ecole Pratique des Hautes Etudes, ICM, H么pital de la Piti茅-Salp锚tri猫re, 75013, Paris, France
  12. D茅partement de G茅n茅tique et Cytog茅n茅tique, AP-HP, G-H Piti茅-Salp锚tri猫re, 47 Bd de l鈥橦么pital, 75013, Paris, France
  10. Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands
  
• ISSN：1432-0533

文摘

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.