Mutant Huntingtin: Nuclear translocation and cytotoxicity mediated by GAPDH

Byoung Il Bae, Makoto R. Hara, Matthew B. Cascio, Cheryl L. Wellington, Michael R. Hayden, Christopher A. Ross, Hyo Chol Ha, Xiao Jiang Li, Solomon H. Snyder, Akira Sawa

Research output: Contribution to journalArticlepeer-review

93 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3405-3409
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number9
StatePublished - Feb 28 2006


  • Huntington's disease
  • Polyglutamine
  • Siah

ASJC Scopus subject areas

  • General


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