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

Jr Nucifora; M. Sasaki; M. F. Peters; Hao Huang; J. K. Cooper; M. Yamada; H. Takahashi; S. Tsuji; J. Troncoso; V. L. Dawson; T. M. Dawson; C. A. Ross

doi:10.1126/science.1056784

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

Jr Nucifora, M. Sasaki, M. F. Peters, Hao Huang, J. K. Cooper, M. Yamada, H. Takahashi, S. Tsuji, J. Troncoso, V. L. Dawson, T. M. Dawson, C. A. Ross

School of Medicine

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English (US)
Pages (from-to)	2423-2428
Number of pages	6
Journal	Science
Volume	291
Issue number	5512
DOIs	https://doi.org/10.1126/science.1056784
State	Published - Mar 23 2001

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title = "Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity",

abstract = "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.",

author = "Jr Nucifora and M. Sasaki and Peters, {M. F.} and Hao Huang and Cooper, {J. K.} and M. Yamada and H. Takahashi and S. Tsuji and J. Troncoso and Dawson, {V. L.} and Dawson, {T. M.} and Ross, {C. A.}",

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doi = "10.1126/science.1056784",

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T1 - Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity

AU - Nucifora, Jr

AU - Sasaki, M.

AU - Peters, M. F.

AU - Huang, Hao

AU - Cooper, J. K.

AU - Yamada, M.

AU - Takahashi, H.

AU - Tsuji, S.

AU - Troncoso, J.

AU - Dawson, V. L.

AU - Dawson, T. M.

AU - Ross, C. A.

PY - 2001/3/23

Y1 - 2001/3/23

N2 - 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.

AB - 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.

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JF - Science

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

Abstract

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