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Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity.

Expanded polyglutamine repeats have been proposed to cause neuronal degeneration in Huntington's disease (HD) and related disorders, through abnormal interactions with other proteins containing short polyglutamine tracts such as the transcriptional coactivator CREB binding protein, CBP. We found that CBP was depleted from its normal nuclear location and was present in polyglutamine aggregates in HD cell culture models, HD transgenic mice, and human HD postmortem brain. Expanded polyglutamine repeats specifically interfere with CBP-activated gene transcription, and overexpression of CBP rescued polyglutamine-induced neuronal toxicity. Thus, polyglutamine-mediated interference with CBP-regulated gene transcription may constitute a genetic gain of function, underlying the pathogenesis of polyglutamine disorders.

Pubmed ID: 11264541


  • Nucifora FC
  • Sasaki M
  • Peters MF
  • Huang H
  • Cooper JK
  • Yamada M
  • Takahashi H
  • Tsuji S
  • Troncoso J
  • Dawson VL
  • Dawson TM
  • Ross CA


Science (New York, N.Y.)

Publication Data

March 23, 2001

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS16375
  • Agency: NINDS NIH HHS, Id: NS34172
  • Agency: NINDS NIH HHS, Id: NS37090
  • Agency: NINDS NIH HHS, Id: NS38144

Mesh Terms

  • Animals
  • Brain
  • CREB-Binding Protein
  • Cell Nucleus
  • Cell Survival
  • Cells, Cultured
  • Humans
  • Huntington Disease
  • Mice
  • Mice, Transgenic
  • Mutation
  • Nerve Tissue Proteins
  • Neurons
  • Nuclear Proteins
  • Peptides
  • Repetitive Sequences, Amino Acid
  • Trans-Activators
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured