Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington's disease

被引：156

作者：

Ju, Tz-Chuen ^{[1
,3
]}

Chen, Hui-Mei ^{[3
]}

Lin, Jiun-Tsai ^{[3
]}

Chang, Ching-Pang ^{[3
]}

Chang, Wei-Cheng ^{[1
]}

Kang, Jheng-Jie ^{[1
]}

Sun, Cheng-Pu ^{[2
]}

Tao, Mi-Hua ^{[3
]}

Tu, Pang-Hsien ^{[3
]}

Chang, Chen ^{[3
]}

Dickson, Dennis W. ^{[4
]}

Chern, Yijuang ^{[1
,3
]}

机构：

[1] Natl Yang Ming Univ, Sch Life Sci, Inst Neurosci, Taipei 112, Taiwan

[2] Natl Yang Ming Univ, Sch Life Sci, Inst Biochem & Mol Biol, Taipei 112, Taiwan

[3] Acad Sinica, Inst Biomed Sci, Div Neurosci, Taipei 11529, Taiwan

[4] Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA

来源：

JOURNAL OF CELL BIOLOGY | 2011年 / 194卷 / 02期

关键词：

ACTIVATED PROTEIN-KINASE; STRESS-INDUCED APOPTOSIS; TRANSGENIC MOUSE MODEL; CENTRAL-NERVOUS-SYSTEM; HUMAN SKELETAL-MUSCLE; CREB-BINDING-PROTEIN; EXPANDED CAG REPEAT; N-TERMINAL KINASE; MUTANT HUNTINGTIN; MITOCHONDRIAL DYSFUNCTION;

D O I：

10.1083/jcb.201105010

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Adenosine monophosphate-activated protein kinase (AMPK) is a major energy sensor that maintains cellular energy homeostasis. Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (Htt) gene. In this paper, we report that activation of the. 1 isoform of AMPK (AMPK-alpha 1) occurred in striatal neurons of humans and mice with HD. Overactivation of AMPK in the striatum caused brain atrophy, facilitated neuronal loss, and increased formation of Htt aggregates in a transgenic mouse model (R6/2) of HD. Such nuclear accumulation of AMPK-alpha 1 was activity dependent. Prevention of nuclear translocation or inactivation of AMPK-alpha 1 ameliorated cell death and down-regulation of Bcl2 caused by mutant Htt (mHtt). Conversely, enhanced expression of Bcl2 protected striatal cells from the toxicity evoked by mHtt and AMPK overactivation. These data demonstrate that aberrant activation of AMPK-alpha 1 in the nuclei of striatal cells represents a new toxic pathway induced by mHtt.

引用

页码：209 / 227

页数：19

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