Mechanisms of rotenone-induced proteasome inhibition.
Mechanisms of rotenone-induced proteasome inhibition.
复制标题
DOI：
10.1016/j.neuro.2010.04.006
复制
发表时间：
2010-08
期刊：
影响因子：
3.4
通讯作者：
Bronstein JM
中科院分区：
文献类型：
--
作者：
Chou AP;Li S;Fitzmaurice AG;Bronstein JM
帕金森病的病因尚不清楚，但似乎涉及线粒体功能障碍，蛋白酶体抑制和环境毒素。已经表明，农药，包括复合物I抑制剂鱼藤酮，引起蛋白酶体抑制，但鱼藤酮诱导的蛋白酶体功能障碍的机制在很大程度上仍然未知。在这项研究中，我们研究了线粒体抑制，氧化应激和微管功能障碍的鱼藤酮诱导的蛋白酶体抑制的潜在介质的作用。在表达EGFP-U降解决定子融合蛋白的HEK和SK-N-MC细胞中测量蛋白酶体活性（26 S），所述EGFP-U降解决定子融合蛋白被蛋白酶体选择性降解。我们发现，复合物I和III抑制导致过氧化物的产生和蛋白酶体活性降低。我们还发现，鱼藤酮增加一氧化氮的生产和一氧化氮和过氧亚硝酸盐导致蛋白酶体抑制。抗氧化剂和一氧化氮合酶抑制剂可减弱鱼藤酮的作用。由于鱼藤酮也可以抑制微管组装，我们测试了一种特定的MT抑制剂，发现它会导致蛋白酶体功能障碍。鱼藤酮还导致20 S蛋白酶体活性和20 S蛋白酶体亚基免疫反应性降低，而亚基mRNA没有变化。总之，这些数据表明鱼藤酮诱导的蛋白酶体活性降低是由于氧化损伤和可能的微管功能障碍引起的蛋白酶体成分降解增加。
The etiology of Parkinson’s disease is unclear but appears to involve mitochondrial dysfunction, proteasome inhibition, and environmental toxins. It has been shown that pesticides, including the complex I inhibitor rotenone, cause proteasome inhibition but the mechanism of rotenone-induced proteasome dysfunction remains largely unknown. In this study, we examined the role of mitochondrial inhibition, oxidative stress, and microtubule dysfunction as potential mediators of rotenone-induced proteasome inhibition. Proteasome activity (26S) was measured in HEK and SK-N-MC cells expressing an EGFP-U degron fusion protein that is selectively degraded by the proteasome. We found that complex I and III inhibition led to the production of peroxides and decreased proteasome activity. We also found that rotenone increased nitric oxide production and nitric oxide and peroxynitrites led to proteasome inhibition. The effects of rotenone were attenuated by anti-oxidants and nitric oxide synthase inhibition. Since rotenone can also inhibit microtubule assembly, we tested a specific MT inhibitor and found it led to proteasome dysfunction. Rotenone also led to a decrease in 20S proteasome activity and 20S proteasome subunit immunoreactivity without a change in subunit mRNA. Together, these data suggest that rotenone-induced decreases in proteasome activity are due to increased degradation of proteasome components secondary to oxidative damage and possibly microtubule dysfunction.
登录
查看更多内容
影响因子：
10.4
作者：
Brown TP;Rumsby PC;Capleton AC;Rushton L;Levy LS
通讯作者：
Levy LS
影响因子：
5.4
作者：
Srivastava, Pallavi;Panda, Dulal
通讯作者：
Panda, Dulal
影响因子：
4.7
作者：
Liu, YB;Fiskum, G;Schubert, D
通讯作者：
Schubert, D
影响因子：
4.1
作者：
TURRENS, JF;BOVERIS, A
通讯作者：
BOVERIS, A
影响因子：
4.7
作者：
Höglinger, GU;Carrard, G;Hirsch, EC
通讯作者：
Hirsch, EC