Kitamura Akira, Kubota Hiroshi, Pack Chan-Gi, Matsumoto Gen, Hirayama Shoshiro, Takahashi Yasuo, Kimura Hiroshi, Kinjo Masataka, Morimoto Richard I, Nagata Kazuhiro
Department of Molecular and Cellular Biology and CREST/JST, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8397, Japan.
Nat Cell Biol. 2006 Oct;8(10):1163-70. doi: 10.1038/ncb1478. Epub 2006 Sep 17.
Polyglutamine (polyQ)-expansion proteins cause neurodegenerative disorders including Huntington's disease, Kennedy's disease and various ataxias. The cytotoxicity of these proteins is associated with the formation of aggregates or other conformationally toxic species. Here, we show that the cytosolic chaperonin CCT (also known as TRiC) can alter the course of aggregation and cytotoxicity of huntingtin (Htt)-polyQ proteins in mammalian cells. Disruption of the CCT complex by RNAi-mediated knockdown enhanced Htt-polyQ aggregate formation and cellular toxicity. Analysis of the aggregation states of the Htt-polyQ proteins by fluorescence correlation spectroscopy revealed that CCT depletion results in the appearance of soluble Htt-polyQ aggregates. Similarly, overexpression of all eight subunits of CCT suppressed Htt aggregation and neuronal cell death. These results indicate that CCT has an essential role in protecting against the cytotoxicity of polyQ proteins by affecting the course of aggregation.
聚谷氨酰胺（polyQ）扩展蛋白会引发神经退行性疾病，包括亨廷顿舞蹈症、肯尼迪病和各种共济失调症。这些蛋白的细胞毒性与聚集体或其他构象毒性物质的形成有关。在此，我们表明胞质伴侣蛋白CCT（也称为TRiC）可改变哺乳动物细胞中亨廷顿蛋白（Htt）-polyQ蛋白的聚集过程和细胞毒性。通过RNA干扰介导的敲低破坏CCT复合物会增强Htt-polyQ聚集体的形成和细胞毒性。利用荧光相关光谱法分析Htt-polyQ蛋白的聚集状态发现，CCT缺失会导致可溶性Htt-polyQ聚集体的出现。同样，CCT所有八个亚基的过表达可抑制Htt聚集和神经元细胞死亡。这些结果表明，CCT通过影响聚集过程在预防polyQ蛋白的细胞毒性方面发挥着重要作用。
