Intersecting pathways to neurodegeneration in Parkinson's disease:: Effects of the pesticide rotenone on DJ-1, α-synuclein, and the ubiquitin-proteasome system
Intersecting pathways to neurodegeneration in Parkinson's disease:: Effects of the pesticide rotenone on DJ-1, α-synuclein, and the ubiquitin-proteasome system
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DOI：
10.1016/j.nbd.2005.12.003
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发表时间：
2006-05-01
影响因子：
6.1
通讯作者：
Greenamyre, JT
中科院分区：
文献类型：
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作者：
Betarbet, R;Canet-Aviles, RA;Greenamyre, JT
散发性帕金森病（PD）最有可能是由环境暴露和遗传易感性的组合引起的，尽管有罕见的单基因形式的疾病。复合物I处的线粒体损伤、氧化应激、α-突触核蛋白聚集和功能失调的蛋白质降解已涉及PD发病机制，但它们如何相互关联尚不清楚。为了进一步评估PD发病机制，我们使用了农药鱼藤酮的慢性低级别复合物I抑制的体内和体外模型。慢性鱼藤酮暴露在体内引起的DJ-1的氧化修饰，α-突触核蛋白的积累，和蛋白酶体损伤。有趣的是，这种作用变得更加区域性限制，使得系统性复合物I抑制最终导致黑质纹状体途径的高度选择性变性。在体外也观察到DJ-1修饰、α-突触核蛋白积累和蛋白酶体功能障碍，这些作用可以用et-生育酚预防。因此，长期暴露于农药和线粒体毒素会使三个系统发挥作用，DJ-1，α-突触核蛋白和泛素-蛋白酶体系统，并意味着线粒体功能障碍和氧化应激将疾病的环境和遗传形式联系起来。(c)2005年爱思唯尔公司All rights reserved.
Sporadic Parkinson's disease (PD) is most likely caused by a combination of environmental exposures and genetic susceptibilities, although there are rare monogenic forms of the disease. Mitochondrial impairment at complex I, oxidative stress, alpha-synuclein aggregation, and dysfunctional protein degradation, have been implicated in PD pathogenesis, but how they are related to each other is unclear. To further evaluated PD pathogenesis here, we used in vivo and in vitro models of chronic low-grade complex I inhibition with the pesticide rotenone. Chronic rotenone exposure in vivo caused oxidative modification of DJ-1, accumulation of alpha-synuclein, and proteasomal impairment. Interestingly, the effects become more regionally restricted such that systemic complex I inhibition eventually results in highly selective degeneration of the nigrostriatal pathway. DJ-1 modifications, alpha-synuclein accumulation, and proteasomal dysfunction were also seen in vitro and these effects could be prevented with et-tocopherol. Thus, chronic exposure to a pesticide and mitochondrial toxin brings into play three systems, DJ-1, alpha-synuclein, and the ubiquitin-proteasome system, and implies that mitochondrial dysfunction and oxidative stress link environmental and genetic forms of the disease. (c) 2005 Elsevier Inc. All rights reserved.