p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease

被引：400

作者：

Bae, BI

Xu, H

Igarashi, S

Fujimuro, M

Agrawal, N

Taya, Y

Hayward, SD

Moran, TH

Montell, C

Ross, CA

Snyder, SH

Sawa, A

机构：

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

[2] Johns Hopkins Univ, Sch Med, Dept Biol Sci, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA

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

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

[6] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

[7] Natl Canc Ctr, Res Inst, Radiobiol Div, Tokyo 1040045, Japan

来源：

NEURON | 2005年 / 47卷 / 01期

关键词：

D O I：

10.1016/j.neuron.2005.06.005

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

We present evidence for a specific role of p53 in the mitochondria-associated cellular dysfunction and behavioral abnormalities of Huntington's disease (HD). Mutant huntingtin (mHtt) with expanded polyglutamine (polyQ) binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity in neuronal cultures. The augmentation is specific, as it occurs with mHtt but not mutant ataxin-1 with expanded polyQ. p53 levels are also increased in the brains of mHtt transgenic (mHtt-Tg) mice and HD patients. Perturbation of p53 by pifithrin-alpha, RNA interference, or genetic deletion prevents mitochondrial membrane depolarization and cytotoxicity in HD cells, as well as the decreased respiratory complex IV activity of mHtt-Tg mice. Genetic deletion of p53 suppresses neurodegeneration in mHtt-Tg flies and neurobehavioral abnormalities of mHtt-Tg mice. Our findings suggest that p53 links nuclear and mitochondrial pathologies characteristic of HD.

引用

页码：29 / 41

页数：13

共 75 条

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