Department of Molecular and Pharmacological Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
Biochem Biophys Res Commun. 2013 Oct 11;440(1):25-30. doi: 10.1016/j.bbrc.2013.09.013. Epub 2013 Sep 8.
Several missense mutations in the protein kinase Cγ (γPKC) gene have been found to cause spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that the mutant γPKC found in SCA14 is misfolded, susceptible to aggregation and cytotoxic. Molecular chaperones assist the refolding and degradation of misfolded proteins and prevention of the proteins' aggregation. In the present study, we found that the expression of mutant γPKC-GFP increased the levels of heat-shock protein 70 (Hsp70) in SH-SY5Y cells. To elucidate the role of this elevation, we investigated the effect of siRNA-mediated knockdown of Hsp70 on the aggregation and cytotoxicity of mutant γPKC. Knockdown of Hsp70 exacerbated the aggregation and cytotoxicity of mutant γPKC-GFP by inhibiting this mutant's degradation. These findings suggest that mutant γPKC increases the level of Hsp70, which protects cells from the mutant's cytotoxicity by enhancing its degradation.
几种蛋白激酶 Cγ（γPKC）基因突变已被发现可导致脊髓小脑共济失调 14 型（SCA14），这是一种常染色体显性神经退行性疾病。我们之前证明，在 SCA14 中发现的突变 γPKC 错误折叠，易聚集和细胞毒性。分子伴侣协助错误折叠蛋白的重折叠和降解以及防止蛋白聚集。在本研究中，我们发现突变型 γPKC-GFP 的表达增加了 SH-SY5Y 细胞中热休克蛋白 70（Hsp70）的水平。为了阐明这种升高的作用，我们研究了 siRNA 介导的 Hsp70 敲低对突变型 γPKC 聚集和细胞毒性的影响。Hsp70 的敲低通过抑制这种突变体的降解而加剧了突变型 γPKC-GFP 的聚集和细胞毒性。这些发现表明，突变型 γPKC 增加了 Hsp70 的水平，通过增强其降解来保护细胞免受突变体的细胞毒性。
