TRiC’s tricks inhibit huntingtin aggregation

Sarah H Shahmoradian,Steven J Ludtke,Judith Frydman,Jesus G Galaz-Montoya,Christoph Spiess,Wah Chiu,Michael F Schmid,Yao Cong,Boxue Ma

doi:10.7554/elife.00710

Sarah H Shahmoradian, Steven J Ludtke + Show 7 more

Open Access

https://doi.org/10.7554/elife.00710

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Journal: eLife	Publication Date: Jul 9, 2013
Citations: 80	License type: CC BY 3.0

Affiliation: Baylor College of Medicine, Stanford University

Abstract

In Huntington's disease, a mutated version of the huntingtin protein leads to cell death. Mutant huntingtin is known to aggregate, a process that can be inhibited by the eukaryotic chaperonin TRiC (TCP1-ring complex) in vitro and in vivo. A structural understanding of the genesis of aggregates and their modulation by cellular chaperones could facilitate the development of therapies but has been hindered by the heterogeneity of amyloid aggregates. Using cryo-electron microscopy (cryoEM) and single particle cryo-electron tomography (SPT) we characterize the growth of fibrillar aggregates of mutant huntingtin exon 1 containing an expanded polyglutamine tract with 51 residues (mhttQ51), and resolve 3-D structures of the chaperonin TRiC interacting with mhttQ51. We find that TRiC caps mhttQ51 fibril tips via the apical domains of its subunits, and also encapsulates smaller mhtt oligomers within its chamber. These two complementary mechanisms provide a structural description for TRiC's inhibition of mhttQ51 aggregation in vitro. DOI:http://dx.doi.org/10.7554/eLife.00710.001.

Highlights

The presence of huntingtin aggregates in the brain correlates strongly with functional deficits in individuals with Huntington’s disease (HD) (DiFiglia et al, 1997)
Amongst the mhtt variants whose susceptibility to TRiC has been previously characterized in vitro and in vivo (Behrends et al, 2006; Tam et al, 2006), our choice of the mhttQ51 variant was guided by the fact that mutations yielding a polyQ tract longer than ∼58Q
Increasing cellular levels of TRiC has a beneficial effect in suppressing mhtt toxicity and aggregation (Behrends et al, 2006; Kitamura et al, 2006; Tam et al, 2006)

Summary

Introduction

The presence of huntingtin aggregates in the brain correlates strongly with functional deficits in individuals with Huntington’s disease (HD) (DiFiglia et al, 1997) These aggregates originate from a mutation in the huntingtin gene that causes an expansion of glutamine (Q) repeats in the huntingtin protein (Zoghbi and Orr, 2009). Understanding how polyQ aggregation is modulated by cellular factors, including molecular chaperones, might lead to therapeutic strategies to treat polyQ pathogenesis. Some chaperones, such as the eukaryotic chaperonin TRiC, are key regulators of protein aggregation (Muchowski and Wacker, 2005; Liebman and Meredith, 2010; Voisine et al, 2010). TRiCs inhibition of mhtt aggregation has been biochemically characterized for several variants both in vitro and in vivo (Kitamura et al, 2006; Tam et al, 2006)

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