Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation.
Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation.
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DOI：
10.1371/journal.pone.0029935
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Mouradian MM
中科院分区：
文献类型：
--
作者：
Lee KW;Zhao X;Im JY;Grosso H;Jang WH;Chan TW;Sonsalla PK;German DC;Ichijo H;Junn E;Mouradian MM
凋亡信号调节激酶1（ASK 1）是丝裂原活化蛋白激酶3家族的一员，在氧化应激时被激活。由ASK 1介导的死亡信号通路被DJ-1抑制，DJ-1与复发性遗传性帕金森病（PD）有关。考虑到DJ-1缺陷会加重线粒体复合物I抑制剂1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）的毒性，我们试图研究ASK 1在MPTP诱导的多巴胺神经元毒性中的直接作用和机制。在本研究中，我们发现，MPTP管理野生型小鼠激活ASK 1在中脑。在ASK 1基因敲除小鼠中，MPTP诱导的运动障碍不太严重，与野生型同窝小鼠相比，纹状体多巴胺含量和黑质多巴胺神经元计数相对保留。此外，在用MPTP攻击的野生型小鼠中观察到的小胶质细胞和星形胶质细胞活化在ASK 1 −/−小鼠中显著减弱。这些数据表明，ASK 1是MPTP诱导的胶质细胞活化的关键参与者，将氧化应激与神经炎症联系起来，这是PD中两个公认的致病因素。这些发现表明，ASK 1是MPTP诱导的毒性的重要效应子，并表明抑制这种激酶是保护PD中多巴胺神经元的合理治疗策略。
Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase 3 family, is activated by oxidative stress. The death-signaling pathway mediated by ASK1 is inhibited by DJ-1, which is linked to recessively inherited Parkinson's disease (PD). Considering that DJ-1 deficiency exacerbates the toxicity of the mitochondrial complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we sought to investigate the direct role and mechanism of ASK1 in MPTP-induced dopamine neuron toxicity. In the present study, we found that MPTP administration to wild-type mice activates ASK1 in the midbrain. In ASK1 null mice, MPTP-induced motor impairment was less profound, and striatal dopamine content and nigral dopamine neuron counts were relatively preserved compared to wild-type littermates. Further, microglia and astrocyte activation seen in wild-type mice challenged with MPTP was markedly attenuated in ASK1−/− mice. These data suggest that ASK1 is a key player in MPTP-induced glial activation linking oxidative stress with neuroinflammation, two well recognized pathogenetic factors in PD. These findings demonstrate that ASK1 is an important effector of MPTP-induced toxicity and suggest that inhibiting this kinase is a plausible therapeutic strategy for protecting dopamine neurons in PD.
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