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Mutant huntingtin: nuclear translocation and cytotoxicity mediated by GAPDH.

http://www.ncbi.nlm.nih.gov/pubmed/16492755

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.

Pubmed ID: 16492755 RIS Download

Mesh terms: Active Transport, Cell Nucleus | Cell Line | Cell Nucleus | Cytoplasm | Gene Expression Regulation | Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) | Humans | Huntington Disease | Mutation | Nerve Tissue Proteins