Letter abstract
Nature Cell Biology 8, 1163 - 1169 (2006)
Published online: 17 September 2006 | doi:10.1038/ncb1478
Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state
Akira Kitamura1, Hiroshi Kubota1, Chan-Gi Pack2, Gen Matsumoto3, Shoshiro Hirayama1, Yasuo Takahashi2,4, Hiroshi Kimura5, Masataka Kinjo2, Richard I. Morimoto3 & Kazuhiro Nagata1
Abstract
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.
- 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.
- Laboratory of Supramolecular Physics, Research Institute for Electronic Science, Hokkaido University, N12W6, Kita-ku, Sapporo, 060-0812, Japan.
- Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
- Olympus Corporation, 2-3 Kuboyama-cho, Hachioji-shi, Tokyo 192-8512, Japan.
- Nuclear Function and Dynamics Unit, HMRO, School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Correspondence to: Hiroshi Kubota1Kazuhiro Nagata1 e-mail: hkubota@frontier.kyoto-u.ac.jp
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