title: Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state.
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.
authors.affiliation: 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.
authors.forename: Akira
authors.initials: A
authors.lastname: Kitamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kubota
authors.forename: Chan-Gi
authors.initials: CG
authors.lastname: Pack
authors.forename: Gen
authors.initials: G
authors.lastname: Matsumoto
authors.forename: Shoshiro
authors.initials: S
authors.lastname: Hirayama
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
authors.forename: Masataka
authors.initials: M
authors.lastname: Kinjo
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagata
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056404:Chaperonin Containing TCP-1; D018833:Chaperonins / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010455:Peptides / Q000633:toxicity*; D011485:Protein Binding
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C533315:Tcp1 protein, mouse; C097188:polyglutamine; D056404:Chaperonin Containing TCP-1; D018833:Chaperonins