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Science 291 (5512): 2423-2428

Copyright © 2001 by the American Association for the Advancement of Science

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

Frederick C. Nucifora Jr.,12 Masayuki Sasaki,3 Matthew F. Peters,1 Hui Huang,3 Jillian K. Cooper,1 Mitsunori Yamada,7 Hitoshi Takahashi,7 Shoji Tsuji,7 Juan Troncoso,6 Valina L. Dawson,2345 Ted M. Dawson,234* Christopher A. Ross124*

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.

1 Division of Neurobiology, Department of Psychiatry,
2 The Program in Cellular and Molecular Medicine,
3 Department of Neurology,
4 Department of Neuroscience,
5 Department of Physiology,
6 Department of Neuropathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
7 Department of Pathology and Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Niigata 951-8585, Japan.
*   To whom correspondence should be addressed. E-mail: tdawson{at}jhmi.edu and caross{at}jhu.edu


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