Paraquat induces dopaminergic dysfunction and proteasome impairment in DJ-1-deficient mice.
Paraquat induces dopaminergic dysfunction and proteasome impairment in DJ-1-deficient mice.
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DOI：
10.1093/hmg/ddm249
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发表时间：
2007-12
影响因子：
3.5
通讯作者：
Wonsuk Yang;Linan Chen;Yunmin Ding;X. Zhuang;U. Kang
中科院分区：
文献类型：
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作者：
Wonsuk Yang;Linan Chen;Yunmin Ding;X. Zhuang;U. Kang
帕金森病（PD）可能是由环境损伤和遗传易感性的复杂相互作用引起的。以前对DJ-1缺陷小鼠的研究已经注意到多巴胺能功能障碍主要发生在老年小鼠中。为了模拟遗传因素和环境因素的相互作用，我们用百草枯处理DJ-1缺陷小鼠。即使在相对年轻的小鼠中，这种组合也会导致多巴胺损失和运动功能障碍。为了确定多巴胺能功能障碍的潜在机制，我们研究了蛋白酶体功能和泛素化蛋白水平。用百草枯处理的DJ-1缺陷小鼠显示蛋白酶体活性降低，泛素化蛋白水平增加。为了进一步研究蛋白酶体功能障碍的机制，测量了19 S ATP酶Rpt 6和20 S β 5的ATP水平和亚基蛋白水平，并注意到腹侧中脑中的ATP水平和亚基蛋白水平降低，但纹状体中没有。最后，一个转录因子，Nrf 2，先前已被证明是由DJ-1调节，并调节20 S β 5水平下降。在用百草枯处理的正常小鼠的脑区中没有观察到这些病理。总之，这项研究提出了可能性，环境和遗传因素可能会合作参与帕金森病脑蛋白酶体损伤的机制。
Parkinson's disease (PD) may be caused by a complex interaction of environmental insults and genetic susceptibilities. Previous studies of DJ-1-deficient mice have noted dopaminergic dysfunction mainly in older mice. To simulate the interaction of genetic factors and environmental factors, we treated DJ-1-deficient mice with paraquat. Even in relatively young mice, this combination produced dopamine loss and motor dysfunction. To determine the potential mechanism for the dopaminergic dysfunction, we investigated the proteasome function and ubiquitinated protein levels. DJ-1-deficient mice treated with paraquat showed decreased proteasome activities and increased ubiquitinated protein levels. To further investigate the mechanism of proteasome dysfunction, ATP levels and subunit protein levels of 19S ATPase Rpt6 and 20S beta5 were measured and noted to be decreased in the ventral midbrain, but not in the striatum. Finally, a transcription factor, Nrf2 that has been previously shown to be regulated by DJ-1 and to regulate 20S beta5 levels was decreased. These pathologies were not observed in brain regions of normal mice treated with paraquat. In conclusion, this study raises the possibility that environmental and genetic factors might cooperatively involve the mechanisms underlying proteasome impairment in PD brains.