title: Differential degradation of full-length and cleaved ataxin-7 fragments in a novel stable inducible SCA7 model.
abstract: Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine repeats, and a common toxic gain-of-function mechanism has been proposed. Proteolytic cleavage of several polyglutamine proteins has been identified and suggested to modulate the polyglutamine toxicity. In this study, we show that full-length and cleaved fragments of the SCA7 disease protein ataxin-7 (ATXN7) are differentially degraded. We found that the ubiquitin-proteosome system (UPS) was essential for the degradation of full-length endogenous ATXN7 or transgenic full-length ATXN7 with a normal or expanded glutamine repeat in both HEK 293T and stable PC12 cells. However, a similar contribution by UPS and autophagy was found for the degradation of proteolytically cleaved ATXN7 fragments. Furthermore, in our novel stable inducible PC12 model, induction of mutant ATXN7 expression resulted in toxicity and this toxicity was worsened by inhibition of either UPS or autophagy. In contrast, pharmacological activation of autophagy could ameliorate the ATXN7-induced toxicity. Based on our findings, we propose that both UPS and autophagy are important for the reduction of mutant ataxin-7-induced toxicity, and enhancing ATXN7 clearance through autophagy could be used as a potential therapeutic strategy in SCA7.
authors.affiliation: Department of Neurochemistry, Stockholm University, 106 91, Stockholm, Sweden. xin.yu@neurochem.su.se
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.forename: Abiodun
authors.initials: A
authors.lastname: Ajayi
authors.forename: Narasimha Rao
authors.initials: NR
authors.lastname: Boga
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Ström
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D042622:DNA Repeat Expansion / Q000235:genetics; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism*; D019076:Transgenes / Q000502:physiology
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593832:Atxn7 protein, rat; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010455:Peptides; C097188:polyglutamine