Free radicals impair the anti-oxidative stress activity of DJ-1 through the formation of SDS-resistant dimer
Free radicals impair the anti-oxidative stress activity of DJ-1 through the formation of SDS-resistant dimer
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DOI：
10.1080/10715762.2017.1324201
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发表时间：
2017-04
影响因子：
3.3
通讯作者：
Tatsuki Yasuda;Takeshi Niki;H. Ariga;Sanae M. M. Iguchi-Ariga-Sanae-M.-M.-Iguchi-Ariga-1395935820
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文献类型：
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作者：
Tatsuki Yasuda;Takeshi Niki;H. Ariga;Sanae M. M. Iguchi-Ariga-Sanae-M.-M.-Iguchi-Ariga-1395935820
DJ-1是家族性帕金森病（PD）的致病基因。DJ-1蛋白的功能丧失被认为是PD发病的原因之一，但DJ-1功能障碍的原因尚不清楚。本研究发现，人多巴胺能神经母细胞瘤SH-SY5Y细胞暴露于大量的超氧化物诱导剂如百草枯和迪喹特后，形成了sds抗性的不可逆的DJ-1蛋白二聚体。PQ氧化还原循环系统的超氧化物和Fenton反应产生的羟基自由基也在体外形成二聚体。因此，我们发现了一种新的现象，自由基直接影响DJ-1形成抗sds二聚体。此外，抗sds二聚体的形成使DJ-1的抗氧化应激活性在体外细胞活力试验和h2o2消除试验中均受损。家族性PD患者中发现的几个DJ-1突变体稳定形成了类似的sds抗性二聚体。这些发现表明，当DJ-1蛋白受到内外应激产生的自由基的直接攻击时，会形成抗sds二聚体，DJ-1受损是散发性PD的原因之一。
Abstract DJ-1 is a causative gene for familial Parkinson’s disease (PD). Loss-of-function of DJ-1 protein is suggested to contribute to the onset of PD, but the causes of DJ-1 dysfunction remain insufficiently elucidated. In this study, we found that the SDS-resistant irreversible dimer of DJ-1 protein was formed in human dopaminergic neuroblastoma SH-SY5Y cells when the cells were exposed to massive superoxide inducers such as paraquat and diquat. The dimer was also formed in vitro by superoxide in PQ redox cycling system and hydroxyl radical produced in Fenton reaction. We, thus, found a novel phenomenon that free radicals directly affect DJ-1 to form SDS-resistant dimers. Moreover, the formation of the SDS-resistant dimer impaired anti-oxidative stress activity of DJ-1 both in cell viability assay and H2O2-elimination assay in vitro. Similar SDS-resistant dimers were steadily formed with several mutants of DJ-1 found in familial PD patients. These findings suggest that DJ-1 is impaired due to the formation of SDS-resistant dimer when the protein is directly attacked by free radicals yielded by external and internal stresses and that the DJ-1 impairment is one of the causes of sporadic PD.