The Chaperonin TRiC Controls Polyglutamine Aggregation and Toxicity Through Subunit-specific Interactions

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2006 Sep 19

PMID 16980959

Citations 167

Authors

Stephen Tam

Ron Geller

Christoph Spiess

Judith Frydman

Affiliations

Soon will be listed here.

Abstract

Misfolding and aggregation of proteins containing expanded polyglutamine repeats underlie Huntington's disease and other neurodegenerative disorders. 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, 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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