Interference by Huntingtin and Atrophin-1 with CBP-Mediated Transcription Leading to Cellular Toxicity

DOI Web Site 33 Citations
  • Frederick C. Nucifora
    Division of Neurobiology, Department of Psychiatry,
  • Masayuki Sasaki
    Department of Neurology,
  • Matthew F. Peters
    Division of Neurobiology, Department of Psychiatry,
  • Hui Huang
    Department of Neurology,
  • Jillian K. Cooper
    Division of Neurobiology, Department of Psychiatry,
  • Mitsunori Yamada
    Department of Pathology and Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Niigata 951-8585, Japan.
  • Hitoshi Takahashi
    Department of Pathology and Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Niigata 951-8585, Japan.
  • Shoji Tsuji
    Department of Pathology and Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Niigata 951-8585, Japan.
  • Juan Troncoso
    Department of Neuropathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205–2196, USA.
  • Valina L. Dawson
    The Program in Cellular and Molecular Medicine,
  • Ted M. Dawson
    The Program in Cellular and Molecular Medicine,
  • Christopher A. Ross
    Division of Neurobiology, Department of Psychiatry,

Abstract

<jats:p>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.</jats:p>

Journal

  • Science

    Science 291 (5512), 2423-2428, 2001-03-23

    American Association for the Advancement of Science (AAAS)

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