title: The autophagy/lysosome pathway is impaired in SCA7 patients and SCA7 knock-in mice.
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.
authors.affiliation: Sorbonne Universités, UPMC Univ. Paris 6, ICM, 75013, Paris, France, sandropfalves@gmail.com.
authors.forename: Sandro
authors.initials: S
authors.lastname: Alves
authors.forename: Florence
authors.initials: F
authors.lastname: Cormier-Dequaire
authors.forename: Martina
authors.initials: M
authors.lastname: Marinello
authors.forename: Thibaut
authors.initials: T
authors.lastname: Marais
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Muriel
authors.forename: Florian
authors.initials: F
authors.lastname: Beaumatin
authors.forename: Fanny
authors.initials: F
authors.lastname: Charbonnier-Beaupel
authors.forename: Khadija
authors.initials: K
authors.lastname: Tahiri
authors.forename: Danielle
authors.initials: D
authors.lastname: Seilhean
authors.forename: Khalid
authors.initials: K
authors.lastname: El Hachimi
authors.forename: Merle
authors.initials: M
authors.lastname: Ruberg
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Martine
authors.initials: M
authors.lastname: Barkats
authors.forename: Wilfred
authors.initials: W
authors.lastname: den Dunnen
authors.forename: Muriel
authors.initials: M
authors.lastname: Priault
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.forename: Annie
authors.initials: A
authors.lastname: Sittler
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000067719:Ataxin-7; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D001921:Brain / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D028044:Phosphate-Binding Proteins; D015398:Signal Transduction / Q000235:genetics; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D018911:Trinucleotide Repeats / Q000235:genetics
chemical_list: C000593829:ATXN7 protein, human; D051017:Apoptosis Regulatory Proteins; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; C491997:BECN1 protein, human; D000071186:Beclin-1; D002352:Carrier Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D028044:Phosphate-Binding Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; C569007:WIPI2 protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases