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

There is still no treatment for polyglutamine disorders, but clearance of mutant proteinsmight 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/ lysosomesystem contributes to the pathogenesis of spinocerebellar ataxiatype 7 (SCA7), caused by expansion of a polyglutamine tractin the ataxin-7 protein, we looked for biochemical, histological and transcriptomic abnormalities in components of the autophagy/ lysosomepathway 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/ lysosomemarkers LC3, LAMP-1, LAMP2and cathepsin-Dwere also found in the cerebellum of the SCA7 knock-in mice. In patients, abnormal accumulations of autophagymarkers were detected in the cerebellum and cerebral cortex of patients, but not in the striatum that is spared in SCA7, suggesting that autophagymight 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 ATG12was increased in PBMC from SCA7 patients in correlation with disease severity. These results provide evidence that the autophagy/ lysosomepathway 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 autophagyin SCA7 and other autophagy/ lysosome-associated neurodegenerative disorders.