1 3 Acta Neuropathol DOI 10.1007/s00401-014-1289-8 ORIGINAL PAPER The autophagy/lysosome pathway is impaired in SCA7 patients and SCA7 knock‑in mice Sandro Alves · 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 Sittler Received: 4 July 2013 / Revised: 18 April 2014 / Accepted: 26 April 2014 © Springer-Verlag Berlin Heidelberg 2014 for biochemical, histological and transcriptomic abnormali- ties 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 accu- mulations 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, abnor- mal 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 Abstract There is still no treatment for polyglutamine disorders, but clearance of mutant proteins might represent a potential therapeutic strategy. Autophagy, the major path- way for organelle and protein turnover, has been implicated in these diseases. To determine whether the autophagy/ lysosome system contributes to the pathogenesis of spi- nocerebellar ataxia type 7 (SCA7), caused by expansion of a polyglutamine tract in the ataxin-7 protein, we looked F. Cormier-Dequaire and M. Marinello contributed equally. Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1289-8) contains supplementary material, which is available to authorized users. S. Alves · F. Cormier-Dequaire · M. Marinello · M.-P. Muriel · F. Charbonnier-Beaupel · K. Tahiri · K. El Hachimi · M. Ruberg · G. Stevanin · A. Brice · A. Durr · J.-C. Corvol · A. Sittler Sorbonne Universités, UPMC Univ. Paris 6, ICM, 75013 Paris, France S. Alves · F. Cormier-Dequaire · M. Marinello · M.-P. Muriel · F. Charbonnier-Beaupel · K. Tahiri · K. El Hachimi · M. Ruberg · G. Stevanin · A. Brice · A. Durr · J.-C. Corvol · A. Sittler Institut National de la Santé et de la Recherche Médicale, U1127, ICM, 75013 Paris, France S. Alves · F. Cormier-Dequaire · M. Marinello · M.-P. Muriel · F. Charbonnier-Beaupel · K. Tahiri · K. El Hachimi · M. Ruberg · G. Stevanin · A. Brice · A. Durr · J.-C. Corvol · A. Sittler Centre National pour la Recherche Scientifique, UMR 7225, ICM, 75013 Paris, France S. Alves (*) · F. Cormier-Dequaire · M. Marinello · M.-P. Muriel · F. Charbonnier-Beaupel · K. Tahiri · K. El Hachimi · M. Ruberg · G. Stevanin · A. Brice · A. Durr · J.-C. Corvol · A. Sittler (*) ICM, Hôpital de la Pitié-Salpêtrière, 47 Bd de l’Hôpital, 75013 Paris, France e-mail: sandropfalves@gmail.com A. Sittler e-mail: annie.sittler@upmc.fr F. Cormier-Dequaire · F. Charbonnier-Beaupel · K. Tahiri · J.-C. Corvol Centre d’Investigation Clinique (CIC-9503), Hôpital de la Pitié- Salpêtrière, 75013 Paris, France T. Marais · M. Barkats Institut National de la Santé et de la Recherche Médicale U974, 75013 Paris, France T. Marais · M. Barkats UPMC-AIM UMR S974, CNRS UMR 7215, Institut de Myologie, 75013 Paris, France F. Beaumatin · M. Priault CNRS, Institut de Biochimie et de Génétique Cellulaire, UMR5095, 33000 Bordeaux, France F. Beaumatin · M. Priault Université de Bordeaux, Institut de Biochimie et de Génétique Cellulaire, UMR5095, 33000 Bordeaux, France