Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 9, Pages 3405-3409Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0511316103
Keywords
Huntington's disease; Siah; polyglutamine
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Funding
- NIDA NIH HHS [DA-00266, DA-00074, P50 DA000266, K05 DA000074] Funding Source: Medline
- NIMH NIH HHS [R01 MH069853, MH-069853] Funding Source: Medline
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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.
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