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

Acta Neuropathologica volume 128, pages 705–722 (2014)Cite this article

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.

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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

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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.

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Affiliations

  1. Sorbonne Universités, UPMC Univ. Paris 6, ICM, 75013, Paris, France

    Sandro Alves, Florence Cormier-Dequaire, Martina Marinello, Marie-Paule Muriel, Fanny Charbonnier-Beaupel, Khadija Tahiri, Khalid El Hachimi, Merle Ruberg, Giovanni Stevanin, Alexis Brice, Alexandra Durr, Jean-Christophe Corvol & Annie Sittler

  2. Institut National de la Santé et de la Recherche Médicale, U1127, ICM, 75013, Paris, France

    Sandro Alves, Florence Cormier-Dequaire, Martina Marinello, Marie-Paule Muriel, Fanny Charbonnier-Beaupel, Khadija Tahiri, Khalid El Hachimi, Merle Ruberg, Giovanni Stevanin, Alexis Brice, Alexandra Durr, Jean-Christophe Corvol & Annie Sittler

  3. Centre National pour la Recherche Scientifique, UMR 7225, ICM, 75013, Paris, France

    Sandro Alves, Florence Cormier-Dequaire, Martina Marinello, Marie-Paule Muriel, Fanny Charbonnier-Beaupel, Khadija Tahiri, Khalid El Hachimi, Merle Ruberg, Giovanni Stevanin, Alexis Brice, Alexandra Durr, Jean-Christophe Corvol & Annie Sittler

  4. Centre d’Investigation Clinique (CIC-9503), Hôpital de la Pitié-Salpêtrière, 75013, Paris, France

    Florence Cormier-Dequaire, Fanny Charbonnier-Beaupel, Khadija Tahiri & Jean-Christophe Corvol

  5. Institut National de la Santé et de la Recherche Médicale U974, 75013, Paris, France

    Thibaut Marais & Martine Barkats

  6. UPMC-AIM UMR S974, CNRS UMR 7215, Institut de Myologie, 75013, Paris, France

    Thibaut Marais & Martine Barkats

  7. CNRS, Institut de Biochimie et de Génétique Cellulaire, UMR5095, 33000, Bordeaux, France

    Florian Beaumatin & Muriel Priault

  8. Université de Bordeaux, Institut de Biochimie et de Génétique Cellulaire, UMR5095, 33000, Bordeaux, France

    Florian Beaumatin & Muriel Priault

  9. Laboratoire de Neuropathologie Escourolle-Hôpital de la Pitié Salpêtrière, AP-HP, 47 Bd de, l’Hôpital, 75013, Paris, France

    Danielle Seilhean

  10. Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands

    Wilfred den Dunnen

  11. Laboratoire de Neurogénétique, Ecole Pratique des Hautes Etudes, ICM, Hôpital de la Pitié-Salpêtrière, 75013, Paris, France

    Khalid El Hachimi & Giovanni Stevanin

  12. Département de Génétique et Cytogénétique, AP-HP, G-H Pitié-Salpêtrière, 47 Bd de l’Hôpital, 75013, Paris, France

    Giovanni Stevanin, Alexis Brice & Alexandra Durr

  13. ICM, Hôpital de la Pitié-Salpêtrière, 47 Bd de l’Hôpital, 75013, Paris, France

    Sandro Alves, Florence Cormier-Dequaire, Martina Marinello, Marie-Paule Muriel, Fanny Charbonnier-Beaupel, Khadija Tahiri, Khalid El Hachimi, Merle Ruberg, Giovanni Stevanin, Alexis Brice, Alexandra Durr, Jean-Christophe Corvol & Annie Sittler

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  1. Sandro Alves
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  2. Florence Cormier-Dequaire
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  14. Wilfred den Dunnen
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  15. Muriel Priault
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  16. Alexis Brice
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  17. Alexandra Durr
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  18. Jean-Christophe Corvol
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  19. Annie Sittler
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Corresponding authors

Correspondence to Sandro Alves or Annie Sittler.

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F. Cormier-Dequaire and M. Marinello contributed equally.

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Alves, S., Cormier-Dequaire, F., Marinello, M. et al. The autophagy/lysosome pathway is impaired in SCA7 patients and SCA7 knock-in mice. Acta Neuropathol 128, 705–722 (2014). https://doi.org/10.1007/s00401-014-1289-8

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Keywords

  • Ataxia
  • Autophagy
  • Lysosome
  • SCA7 knock-in mouse
  • Patients
  • Transcriptome