Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state

Akira Kitamura, Hiroshi Kubota*, Chan Gi Pack, Gen Matsumoto, Shoshiro Hirayama, Yasuo Takahashi, Hiroshi Kimura, Masataka Kinjo, Richard I. Morimoto, Kazuhiro Nagata

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

207 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1163-1170
Number of pages8
JournalNature Cell Biology
Volume8
Issue number10
DOIs
StatePublished - Oct 2006

ASJC Scopus subject areas

  • Cell Biology

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