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

Frederick Nucifora, M. Sasaki, M. F. Peters, H. Huang, J. K. Cooper, M. Yamada, H. Takahashi, S. Tsuji, Juan C Troncoso, Valina Dawson, Ted M Dawson, Christopher A Ross

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)2423-2428
Number of pages6
JournalScience
Volume291
Issue number5512
DOIs
StatePublished - Mar 23 2001
Externally publishedYes

Fingerprint

Huntington Disease
CREB-Binding Protein
polyglutamine
atrophin-1
Transgenic Mice
Genes
Cell Culture Techniques
Brain
Proteins

ASJC Scopus subject areas

  • General

Cite this

Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. / Nucifora, Frederick; Sasaki, M.; Peters, M. F.; Huang, H.; Cooper, J. K.; Yamada, M.; Takahashi, H.; Tsuji, S.; Troncoso, Juan C; Dawson, Valina; Dawson, Ted M; Ross, Christopher A.

In: Science, Vol. 291, No. 5512, 23.03.2001, p. 2423-2428.

Research output: Contribution to journalArticle

Nucifora, Frederick ; Sasaki, M. ; Peters, M. F. ; Huang, H. ; Cooper, J. K. ; Yamada, M. ; Takahashi, H. ; Tsuji, S. ; Troncoso, Juan C ; Dawson, Valina ; Dawson, Ted M ; Ross, Christopher A. / Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. In: Science. 2001 ; Vol. 291, No. 5512. pp. 2423-2428.
@article{5aa86d2fd269498c820b39529ceb784f,
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 = "Frederick Nucifora and M. Sasaki and Peters, {M. F.} and H. Huang and Cooper, {J. K.} and M. Yamada and H. Takahashi and S. Tsuji and Troncoso, {Juan C} and Valina Dawson and Dawson, {Ted M} and Ross, {Christopher A}",
year = "2001",
month = "3",
day = "23",
doi = "10.1126/science.1056784",
language = "English (US)",
volume = "291",
pages = "2423--2428",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "5512",

}

TY - JOUR

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

AU - Nucifora, Frederick

AU - Sasaki, M.

AU - Peters, M. F.

AU - Huang, H.

AU - Cooper, J. K.

AU - Yamada, M.

AU - Takahashi, H.

AU - Tsuji, S.

AU - Troncoso, Juan C

AU - Dawson, Valina

AU - Dawson, Ted M

AU - Ross, Christopher 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.

UR - http://www.scopus.com/inward/record.url?scp=0035937523&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035937523&partnerID=8YFLogxK

U2 - 10.1126/science.1056784

DO - 10.1126/science.1056784

M3 - Article

C2 - 11264541

AN - SCOPUS:0035937523

VL - 291

SP - 2423

EP - 2428

JO - Science

JF - Science

SN - 0036-8075

IS - 5512

ER -