Yang Wonsuk, Chen Linan, Ding Yunmin, Zhuang Xiaoxi, Kang Un Jung
Department of neurology, The University of Chicago, IL 60637, USA.
Hum Mol Genet. 2007 Dec 1;16(23):2900-10. doi: 10.1093/hmg/ddm249. Epub 2007 Sep 6.
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.
帕金森病（PD）可能由环境损伤与遗传易感性的复杂相互作用引起。先前对DJ - 1基因缺陷小鼠的研究主要在老年小鼠中发现了多巴胺能功能障碍。为了模拟遗传因素与环境因素的相互作用，我们用百草枯处理DJ - 1基因缺陷小鼠。即使在相对年轻的小鼠中，这种联合处理也导致了多巴胺丧失和运动功能障碍。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基因缺陷小鼠表现出蛋白酶体活性降低和泛素化蛋白水平升高。为了进一步研究蛋白酶体功能障碍的机制，我们测量了腹侧中脑19S ATP酶Rpt6和20S β5的ATP水平和亚基蛋白水平，发现其降低，但纹状体中未降低。最后，先前已证明受DJ - 1调节并调节20S β5水平的转录因子Nrf2减少。在用百草枯处理的正常小鼠脑区未观察到这些病变。总之，本研究提出了环境和遗传因素可能协同参与PD脑蛋白酶体损伤潜在机制的可能性。
