Reduced anti-oxidative stress activities of DJ-1 mutants found in Parkinson's disease patients
Reduced anti-oxidative stress activities of DJ-1 mutants found in Parkinson's disease patients
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DOI：
10.1016/j.bbrc.2004.05.187
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发表时间：
2004-07-23
影响因子：
3.1
通讯作者：
Ariga, H
中科院分区：
文献类型：
--
作者：
Takahashi-Niki, K;Niki, T;Ariga, H
DJ-1 是一种多功能蛋白，在转录调节和抗氧化应激中发挥作用，其功能丧失被认为会导致帕金森病的发作。我们之前曾报道过，L166P（一种在帕金森病患者中发现的突变 DJ-1）没有预防过氧化氢 (H2O2) 诱导的细胞死亡的活性。在这项研究中，我们分析了帕金森病患者中发现的其他 DJ-1 突变体，包括 M261、R98Q、D149A 以及 L166P。我们首先发现所有突变体均与野生型DJ-1形成异二聚体，而除L166P外的所有突变体均形成同二聚体。然后我们发现 M261 和 L166P（两者均源自 DJ-I 基因的纯合突变）不稳定，并且在蛋白酶体抑制剂 MG132 存在的情况下，它们的稳定性部分得到恢复。稳定表达这些DJ-I突变体的NIH3T3细胞系表明，L166P和C106S细胞系（DJ-1蛋白酶活性（-）的突变体）甚至没有清除内源产生的活性氧的活性。这些细胞系还表明，所有突变体消除外源添加的 H2O2 的活性均降低，并且这些活性（D149A 除外）与防止 H2O2 诱导的细胞死亡的活性平行。 (C) 2004 Elsevier Inc. 保留所有权利。
DJ-1 is a multi-functional protein that plays roles in transcriptional regulation and anti-oxidative stress, and loss of its function is thought to result in onset of Parkinson's disease. We have previously reported that L166P, a mutant DJ-1 found in Parkinson's disease patients, had no activity to prevent hydrogen peroxide (H2O2)-induced cell death. In this study, we analyzed other mutants of DJ-1 found in Parkinson's disease patients, including M261, R98Q, and D149A, as well as L166P. We first found that all of the mutants made heterodimers with wild-type DJ-1, while all of the mutants except for L166P made homodimers. We then found that M261 and L166P, both of which are derived from homozygous mutations of the DJ-I gene, were unstable and that their stabilities were recovered, in part, in the presence of proteasome inhibitor, MG132. NIH3T3 cell lines stably expressing these mutants of DJ-I showed that cell lines of L166P and C106S, a mutant for protease activity (-) of DJ-1, had no activity to scavenge even endogenously producing reactive oxygen species. These cell lines also showed that all of the mutants had reduced activities to eliminate exogenously added H2O2 and that these activities, except for that of D149A, were parallel to those preventing H2O2-induced cell death. (C) 2004 Elsevier Inc. All rights reserved.