Liu Fang, Hindupur Jagadish, Nguyen Jamie L, Ruf Katie J, Zhu Junyi, Schieler Jeremy L, Bonham Connie C, Wood Karl V, Davisson V Jo, Rochet Jean-Christophe
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Free Radic Biol Med. 2008 Aug 1;45(3):242-55. doi: 10.1016/j.freeradbiomed.2008.03.022. Epub 2008 Apr 11.
Parkinson's disease (PD) is a neurologic disorder characterized by dopaminergic cell death in the substantia nigra. PD pathogenesis involves mitochondrial dysfunction, proteasome impairment, and alpha-synuclein aggregation, insults that may be especially toxic to oxidatively stressed cells including dopaminergic neurons. The enzyme methionine sulfoxide reductase A (MsrA) plays a critical role in the antioxidant response by repairing methionine-oxidized proteins and by participating in cycles of methionine oxidation and reduction that have the net effect of consuming reactive oxygen species. Here, we show that MsrA suppresses dopaminergic cell death and protein aggregation induced by the complex I inhibitor rotenone or mutant alpha-synuclein, but not by the proteasome inhibitor MG132. By comparing the effects of MsrA and the small-molecule antioxidants N-acetylcysteine and vitamin E, we provide evidence that MsrA protects against PD-related stresses primarily via methionine sulfoxide repair rather than by scavenging reactive oxygen species. We also demonstrate that MsrA efficiently reduces oxidized methionine residues in recombinant alpha-synuclein. These findings suggest that enhancing MsrA function may be a reasonable therapeutic strategy in PD.
帕金森病（PD）是一种神经疾病，其特征是黑质中的多巴胺能细胞死亡。PD的发病机制涉及线粒体功能障碍、蛋白酶体损伤和α-突触核蛋白聚集，这些损伤对包括多巴胺能神经元在内的氧化应激细胞可能具有特别的毒性。甲硫氨酸亚砜还原酶A（MsrA）通过修复甲硫氨酸氧化的蛋白质以及参与甲硫氨酸氧化和还原循环（其净效应是消耗活性氧）在抗氧化反应中发挥关键作用。在这里，我们表明MsrA可抑制由复合体I抑制剂鱼藤酮或突变型α-突触核蛋白诱导的多巴胺能细胞死亡和蛋白质聚集，但不能抑制蛋白酶体抑制剂MG132诱导的这些现象。通过比较MsrA与小分子抗氧化剂N-乙酰半胱氨酸和维生素E的作用，我们提供证据表明MsrA主要通过甲硫氨酸亚砜修复而非清除活性氧来抵御与PD相关的应激。我们还证明MsrA能有效减少重组α-突触核蛋白中的氧化甲硫氨酸残基。这些发现表明增强MsrA功能可能是PD的一种合理治疗策略。
