Nuclear translocation of AMPK-alpha1 potentiates striatal neurodegeneration in Huntington's disease.
Nuclear translocation of AMPK-alpha1 potentiates striatal neurodegeneration in Huntington's disease.
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DOI：
10.1083/jcb.201105010
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发表时间：
2011-07-25
期刊：
影响因子：
--
通讯作者：
Chern Y
中科院分区：
文献类型：
--
作者：
Ju TC;Chen HM;Lin JT;Chang CP;Chang WC;Kang JJ;Sun CP;Tao MH;Tu PH;Chang C;Dickson DW;Chern Y
在亨廷顿病模型中，AMPK-α1的核积聚可诱导脑萎缩、神经元丢失和Htt聚集体的形成。腺苷单磷酸活化蛋白激酶（AMPK）是维持细胞能量稳态的主要能量传感器。亨廷顿氏病（HD）是一种由亨廷顿蛋白（Htt）基因CAG重复扩增引起的神经退行性疾病。在本文中，我们报道了AMPK α1亚型（AMPK-α1）在人类和HD小鼠纹状体神经元中被激活。在HD转基因小鼠模型（R6/2）中，纹状体中AMPK的过度激活导致脑萎缩，促进神经元丢失，并增加Htt聚集体的形成。AMPK-α1的核积累具有活性依赖性。防止核易位或AMPK-α1失活可改善突变体Htt （mHtt）引起的细胞死亡和Bcl2下调。相反，Bcl2表达的增强保护纹状体细胞免受mHtt和AMPK过度激活引起的毒性。这些数据表明，纹状体细胞核AMPK-α1的异常激活代表了mHtt诱导的一种新的毒性途径。
Nuclear accumulation of AMPK-α1 induces brain atrophy, neuronal loss, and formation of Htt aggregates in a Huntington’s disease model. 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 α1 isoform of AMPK (AMPK-α1) 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-α1 was activity dependent. Prevention of nuclear translocation or inactivation of AMPK-α1 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-α1 in the nuclei of striatal cells represents a new toxic pathway induced by mHtt.
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影响因子：
4.7
作者：
Chou, SY;Lee, YC;Chern, YJ
通讯作者：
Chern, YJ
影响因子：
3.5
作者：
Chiang, Ming-Chang;Chen, Hui-Mei;Chern, Yijuang
通讯作者：
Chern, Yijuang
影响因子：
12.4
作者：
Chen, Chun-Chi;Sun, Cheng-Pu;Tao, Mi-Hua
通讯作者：
Tao, Mi-Hua
DOI：
10.1073/pnas.0705070104
发表时间：
2007-07-17
影响因子：
11.1
作者：
Jaeger, Sibylle;Handschin, Christoph;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.
影响因子：
7.4
作者：
Ju, TC;Chen, SD;Yang, DI
通讯作者：
Yang, DI