Harnessing Chaperone-mediated Autophagy for the Selective Degradation of Mutant Huntingtin Protein

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2010 Mar 2

PMID 20190739

Citations 125

Authors

Peter O Bauer

Anand Goswami

Hon Kit Wong

Misako Okuno

Masaru Kurosawa

Mizuki Yamada

Haruko Miyazaki

Gen Matsumoto

Yoshihiro Kino

Yoshitaka Nagai

Nobuyuki Nukina

Affiliations

Soon will be listed here.

Abstract

Huntington's Disease (HD) is a dominantly inherited pathology caused by the accumulation of mutant huntingtin protein (HTT) containing an expanded polyglutamine (polyQ) tract. As the polyglutamine binding peptide 1 (QBP1) is known to bind an expanded polyQ tract but not the polyQ motif found in normal HTT, we selectively targeted mutant HTT for degradation by expressing a fusion molecule comprising two copies of QBP1 and copies of two different heat shock cognate protein 70 (HSC70)-binding motifs in cellular and mouse models of HD. Chaperone-mediated autophagy contributed to the specific degradation of mutant HTT in cultured cells expressing the construct. Intrastriatal delivery of a virus expressing the fusion molecule ameliorated the disease phenotype in the R6/2 mouse model of HD. Similar adaptor molecules comprising HSC70-binding motifs fused to an appropriate structure-specific binding agent(s) may have therapeutic potential for treating diseases caused by misfolded proteins other than those with expanded polyQ tracts.

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