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

被引：852

作者：

Nucifora, FC

Sasaki, M

Peters, MF

Huang, H

Cooper, JK

Yamada, M

Takahashi, H

Tsuji, S

Troncoso, J

Dawson, VL

Dawson, TM ^{[1
]}

Ross, CA

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Psychiat, Div Neurobiol, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Dept Neuropathol, Baltimore, MD 21205 USA

[7] Niigata Univ, Brain Res Inst, Dept Pathol & Neurol, Niigata 9518585, Japan

来源：

SCIENCE | 2001年 / 291卷 / 5512期

关键词：

D O I：

10.1126/science.1056784

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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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收藏

页码：2423 / 2428

页数：6

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