Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson's disease
Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson's disease
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DOI：
10.1016/j.neuron.2007.05.033
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发表时间：
2007-07-05
期刊：
影响因子：
16.2
通讯作者：
Park, David S.
中科院分区：
文献类型：
--
作者：
Qu, Dianbo;Rashidian, Juliet;Park, David S.
我们之前报道过calpain介导的Cdk5激活对于线粒体毒素诱导的多巴胺能性死亡至关重要。在这里，我们报告一个调节这种损失的目标。Prx2是一种抗氧化酶，与Cdk5/p35结合。在MPP+和/或MPTP处理的动物神经元中，Prx2以calpain/Cdk5/p35依赖的方式在T89位点磷酸化。这种磷酸化降低了Prx2过氧化物酶的活性。与此一致的是，p35（-/-）神经元在MPP+处理后表现出氧化应激降低。Prx2和Prx2T89A的表达，而不是磷酸化模拟Prx2T89E，在线粒体损伤后保护培养和成年神经元。最后，Prx2的下调增加了氧化应激和对MPP+的敏感性。我们提出了一个线粒体毒素导致calpain介导的Cdk5激活、Prx2活性降低和消除ROS能力下降的机制模型。重要的是，与对照组相比，帕金森病患者死后组织的黑神经细胞中也会出现Prx2磷酸化的增加，这表明该途径在人类疾病中的相关性。
We reported previously that calpain-mediated Cdk5 activation is critical for mitochondrial toxin-induced dopaminergic death. Here, we report a target that mediates this loss. Prx2, an antioxidant enzyme, binds Cdk5/p35. Prx2 is phosphorylated at T89 in neurons treated with MPP+ and/or MPTP in animals in a calpain/Cdk5/p35-dependent manner. This phosphorylation reduces Prx2 peroxidase activity. Consistent with this, p35(-/-) neurons show reduced oxidative stress upon MPP+ treatment. Expression of Prx2 and Prx2T89A, but not the phosphorylation mimic Prx2T89E, protects cultured and adult neurons following mitochondrial insult. Finally, downregulation of Prx2 increases oxidative stress and sensitivity to MPP+. We propose a mechanistic model by which mitochondrial toxin leads to calpain-mediated Cdk5 activation, reduced Prx2 activity, and decreased capacity to eliminate ROS. Importantly, increased Prx2 phosphorylation also occurs in nigral neurons from postmortem tissue from Parkinson's disease patients when compared to control, suggesting the relevance of this pathway in the human condition.