Journal
NATURE CELL BIOLOGY
Volume 8, Issue 10, Pages 1155-U211Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1477
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Funding
- NIGMS NIH HHS [R37 GM056433, R01 GM056433-09, GM74074, R01 GM074074-02, R01 GM056433-12, R01 GM074074-01S1, R01 GM056433-10S1, R01 GM056433-10, R01 GM074074, R01 GM056433-07, R01 GM074074-03, R01 GM056433, R01 GM056433-03, R01 GM056433-04, R01 GM056433-06, R01 GM074074-04, R01 GM056433-08, R01 GM074074-01, R01 GM056433-05, R01 GM056433-11, GM56433] Funding Source: Medline
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Misfolding and aggregation of proteins containing expanded polyglutamine repeats underlie Huntington's disease and other neurodegenerative disorders(1). Here, we show that the hetero-oligomeric chaperonin TRiC (also known as CCT) physically interacts with polyglutamine-expanded variants of huntingtin (Htt) and effectively inhibits their aggregation. Depletion of TRiC enhances polyglutamine aggregation in yeast and mammalian cells. Conversely, overexpression of a single TRiC subunit, CCT1, is sufficient to remodel Htt-aggregate morphology in vivo and in vitro, and reduces Htt-induced toxicity in neuronal cells. Because TRiC acts during de novo protein biogenesis(2), this chaperonin may have an early role preventing Htt access to pathogenic conformations. Based on the specificity of the Htt - CCT1 interaction, the CCT1 substrate-binding domain may provide a versatile scaffold for therapeutic inhibitors of neurodegenerative disease.
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