Wang Xue-Feng, Li Sharon, Chou Arthur P, Bronstein Jeff M
Department of Neurology, University of California at Los Angeles David Geffen School of Medicine, Los Angeles, CA 90095, USA.
Neurobiol Dis. 2006 Jul;23(1):198-205. doi: 10.1016/j.nbd.2006.02.012. Epub 2006 Apr 19.
Epidemiological studies have suggested a correlation of pesticides and Parkinson's disease (PD) while genetic and biochemical studies have implicated the ubiquitin-proteasome system (UPS) in the pathogenesis of PD. In the present studies, we tested the hypothesis that pesticide exposure increases the risk of developing PD by inhibiting the UPS. The effects of pesticides on proteasome activity were examined in SK-N-MC neuroblastoma cells overexpressing a GFP-conjugated proteasome degradation signal, GFP(u). Six out of 25 representative pesticides, including rotenone, ziram, diethyldithiocarbamate, endosulfan, benomyl, and dieldrin, showed inhibitory effects on proteasome activities at low concentrations (10 nM to 10 microM). Unlike proteasome inhibitors, they did not inhibit 20 S proteasome activities in cell lysates. Except for rotenone, the other five pesticides did not induce significantly cellular oxidative stress. The cytotoxic effects of these pesticides were closely correlated with proteasome inhibition. Our results suggest proteasome inhibition as a potential mechanism for the epidemiological association of pesticides and PD.
流行病学研究表明农药与帕金森病（PD）之间存在关联，而遗传学和生物化学研究则表明泛素 - 蛋白酶体系统（UPS）与PD的发病机制有关。在本研究中，我们检验了以下假设：农药暴露通过抑制UPS增加患PD的风险。在过表达绿色荧光蛋白（GFP）偶联蛋白酶体降解信号GFP（u）的SK - N - MC神经母细胞瘤细胞中检测了农药对蛋白酶体活性的影响。25种代表性农药中的6种，包括鱼藤酮、福美锌、二乙基二硫代氨基甲酸盐、硫丹、苯菌灵和狄氏剂，在低浓度（10 nM至10 microM）时对蛋白酶体活性有抑制作用。与蛋白酶体抑制剂不同，它们不抑制细胞裂解物中的20S蛋白酶体活性。除鱼藤酮外，其他五种农药均未显著诱导细胞氧化应激。这些农药的细胞毒性作用与蛋白酶体抑制密切相关。我们的结果表明蛋白酶体抑制是农药与PD流行病学关联的潜在机制。
