Activation of Hsp70 Reduces Neurotoxicity by Promoting Polyglutamine Protein Degradation

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2012 Dec 11

PMID 23222885

Citations 105

Authors

Adrienne M Wang

Yoshinari Miyata

Susan Klinedinst

Hwei-Ming Peng

Jason P Chua

Tomoko Komiyama

Xiaokai Li

Yoshihiro Morishima

Diane E Merry

William B Pratt

Yoichi Osawa

Catherine A Collins

Jason E Gestwicki

Andrew P Lieberman

Affiliations

Soon will be listed here.

Abstract

We sought new strategies to reduce amounts of the polyglutamine androgen receptor (polyQ AR) and achieve benefits in models of spinobulbar muscular atrophy, a protein aggregation neurodegenerative disorder. Proteostasis of the polyQ AR is controlled by the heat shock protein 90 (Hsp90)- and Hsp70-based chaperone machinery, but mechanisms regulating the protein's turnover are incompletely understood. We demonstrate that overexpression of Hsp70 interacting protein (Hip), a co-chaperone that enhances binding of Hsp70 to its substrates, promotes client protein ubiquitination and polyQ AR clearance. Furthermore, we identify a small molecule that acts similarly to Hip by allosterically promoting Hsp70 binding to unfolded substrates. Like Hip, this synthetic co-chaperone enhances client protein ubiquitination and polyQ AR degradation. Both genetic and pharmacologic approaches targeting Hsp70 alleviate toxicity in a Drosophila model of spinobulbar muscular atrophy. These findings highlight the therapeutic potential of allosteric regulators of Hsp70 and provide new insights into the role of the chaperone machinery in protein quality control.

Citing Articles

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