Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein

Peter O. Bauer, Anand Goswami, Hon Kit Wong, Misako Okuno, Masaru Kurosawa, Mizuki Yamada, Haruko Miyazaki, Gen Matsumoto, Yoshihiro Kino, Yoshitaka Nagai, Nobuyuki Nukina

Research output: Contribution to journalArticlepeer-review

180 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)256-263
Number of pages8
JournalNature Biotechnology
Issue number3
Publication statusPublished - Mar 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering


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