Buck Institute for Age Research, Novato, CA, USA.
Autophagy. 2010 Feb;6(2):312-4. doi: 10.4161/auto.6.2.11139. Epub 2010 Feb 6.
Recent studies have highlighted the importance of the lysosome in degrading proteins that misfold in neurodegenerative diseases. In this study we explore the role for autophagy in the clearance of an N-terminal caspase-7-generated fragment of ataxin-7, a protein with a pathogenic polyglutamine (polyQ) expansion in the neurodegenerative disease spinocerebellar ataxia 7 (SCA7). Using both cellular and transgenic mouse models of SCA7 we show that the stability of wild-type ataxin-7 is modified by macroautophagy, but not by proteasomal, inhibition, whereas both autophagy and proteasomal degradation have little effect on polyQ-expanded ataxin-7. We also create a post-translational modification-deficient ataxin-7 mutant that has increased protein turnover of both wild-type and polyQ-expanded ataxin-7, mediated through the autophagy pathway. Histological analysis reveals that wild-type ataxin-7 colocalizes with markers of chaperone-mediated autophagy (CMA) and macroautophagy, indicating that both of these mechanisms may play a role in the clearance of ataxin-7. Furthermore, there is an increase in LC3, a marker of autophagy initiation, in the cerebellum of SCA7 transgenic mice. Our findings indicate that the ataxin-7 fragment may be cleared via autophagy and that this process is altered in SCA7. Identification of the different types of autophagy involved in ataxin-7 turnover and the influence of post-translational modifications on these processes will be pursued in future studies.
最近的研究强调了溶酶体在降解神经退行性疾病中错误折叠蛋白质的重要性。在这项研究中，我们探讨了自噬在清除 ataxin-7 的 N 端半胱天冬酶-7 生成片段中的作用，ataxin-7 是一种具有致病性多聚谷氨酰胺（polyQ）扩展的蛋白，在神经退行性疾病脊髓小脑共济失调 7（SCA7）中。我们使用 SCA7 的细胞和转基因小鼠模型表明，野生型 ataxin-7 的稳定性受巨自噬修饰，但不受蛋白酶体抑制修饰，而自噬和蛋白酶体降解对 polyQ 扩展的 ataxin-7 几乎没有影响。我们还创建了一种翻译后修饰缺陷的 ataxin-7 突变体，该突变体增加了 both wild-type 和 polyQ-expanded ataxin-7 的蛋白周转率，通过自噬途径介导。组织学分析表明，野生型 ataxin-7 与伴侣介导的自噬（CMA）和巨自噬的标志物共定位，表明这两种机制都可能在 ataxin-7 的清除中发挥作用。此外，SCA7 转基因小鼠小脑的 LC3（自噬起始的标志物）增加。我们的发现表明，ataxin-7 片段可能通过自噬清除，并且该过程在 SCA7 中发生改变。未来的研究将致力于鉴定涉及 ataxin-7 周转率的不同类型的自噬以及翻译后修饰对这些过程的影响。
