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- Title
Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein.
- Authors
Bauer, Peter O; Goswami, Anand; Wong, Hon Kit; Okuno, Misako; Kurosawa, Masaru; Yamada, Mizuki; Miyazaki, Haruko; Matsumoto, Gen; Kino, Yoshihiro; Nagai, Yoshitaka; Nukina, Nobuyuki
- 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.
- Publication
Nature biotechnology, 2010, Vol 28, Issue 3, p256
- ISSN
1546-1696
- Publication type
Journal Article
- DOI
10.1038/nbt.1608