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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12031-012-9722-8) contains supplementary material, which is available to authorized users.
Highlights
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by neuronal death in the retina, cerebellum, and brainstem (Harding and Deufel 1993)
The disease is caused by expansion of an unstable CAG repeat in the 5′-end of the SCA7 gene resulting in an expanded polyglutamine domain in the ataxin-7 (ATXN7) protein (David et al 1997)
Expression of Expanded ATXN7 in a Novel Inducible PC12 Cell Line Leads to Aggregation and Toxicity
Summary
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by neuronal death in the retina, cerebellum, and brainstem (Harding and Deufel 1993). The exact role of ATXN7 in STAGA and how this function is affected by the polyglutamine expansion are still unclear (for review, see McCullough and Grant 2010). Besides SCA7, eight other neurodegenerative disorders including Huntington’s disease (HD), dentatorubral pallidolusian atrophy, spinal bulbar muscular atrophy, and SCA13, 6, and 17, caused by CAG/glutamine expansions, have been identified (Katsuno et al 2008). These disorders are commonly known as polyglutamine (polyQ) diseases and are characterized by aggregation of the expanded polyQ protein into nuclear and/or cytoplasmic inclusions in the neurons of patients. A correlation between the ability of the polyglutamine protein to aggregate and cause toxicity has been shown; whether misfolded monomers, oligomers, or large inclusions are the major toxic species is still unclear (Davies and Scherzinger 1997; Hands and Wyttenbach 2010; Scherzinger et al 1999)
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