Department of Neurochemistry, Stockholm University, 106 91, Stockholm, Sweden.
J Mol Neurosci. 2012 Jun;47(2):219-33. doi: 10.1007/s12031-012-9722-8. Epub 2012 Feb 25.
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.
脊髓小脑性共济失调 7 型（SCA7）是由扩展的多聚谷氨酰胺重复引起的九种神经退行性疾病之一，提出了一种常见的毒性获得性功能机制。已经鉴定出几种多聚谷氨酰胺蛋白的蛋白水解切割，并提出其可调节多聚谷氨酰胺毒性。在这项研究中，我们表明 SCA7 疾病蛋白 ataxin-7（ATXN7）的全长和切割片段以不同的方式降解。我们发现泛素蛋白酶体系统（UPS）对于全长内源性 ATXN7 或在 HEK 293T 和稳定的 PC12 细胞中具有正常或扩展谷氨酰胺重复的转基因全长 ATXN7 的降解是必需的。然而，UPS 和自噬对于切割的 ATXN7 片段的降解都有类似的贡献。此外，在我们的新型稳定诱导的 PC12 模型中，诱导突变型 ATXN7 表达导致毒性，并且 UPS 或自噬的抑制会使这种毒性恶化。相比之下，自噬的药理学激活可以改善 ATXN7 诱导的毒性。基于我们的发现，我们提出 UPS 和自噬对于减少突变型 ataxin-7 诱导的毒性都很重要，并且通过自噬增强 ATXN7 的清除可能成为 SCA7 的潜在治疗策略。
