Chaperone-mediated remodelling of mutant huntingtin

Abstract

Huntington's disease is caused by the trinucleotide repeat CAG expansion in the huntingtin gene, resulting in an N-terminal polyglutamine (polyQ) tract that renders the huntingtin protein (HTT) prone to misfolding and aggregation. Although polyQ expansion is an intrinsic driver of aggregation, the folding trajectory of HTT is strongly shaped by molecular chaperones that detect all conformational entities of HTT and as such bind to soluble HTT and suppress β-sheet formation, target HTT for proteasomal degradation and resolubilize HTT fibrils by disaggregation. This review summarizes recent in vitro and in vivo data on the role of molecular chaperones in the HTTExon1 folding landscape and its cooperation with the proteolytic pathways.

This article is part of the Theo Murphy meeting issue ‘ProteostaSys: a systems view of proteostasis'.