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Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3405-9. Epub 2006 Feb 21.

Mutant huntingtin: nuclear translocation and cytotoxicity mediated by GAPDH.

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  • 1Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Abstract

The pathophysiology of Huntington's disease reflects actions of mutant Huntingtin (Htt) (mHtt) protein with polyglutamine repeats, whose N-terminal fragment translocates to the nucleus to elicit neurotoxicity. We establish that the nuclear translocation and associated cytotoxicity of mHtt reflect a ternary complex of mHtt with GAPDH and Siah1, a ubiquitin-E3-ligase. Overexpression of GAPDH or Siah1 enhances nuclear translocation of mHtt and cytotoxicity, whereas GAPDH mutants that cannot bind Siah1 prevent translocation. Depletion of GAPDH or Siah1 by RNA interference diminishes nuclear translocation of mHtt.

PMID:
16492755
[PubMed - indexed for MEDLINE]
PMCID:
PMC1413934
Free PMC Article

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