DJ-1 Interacts with and Regulates Paraoxonase-2, an Enzyme Critical for Neuronal Survival in Response to Oxidative Stress
DJ-1 Interacts with and Regulates Paraoxonase-2, an Enzyme Critical for Neuronal Survival in Response to Oxidative Stress
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DOI：
10.1371/journal.pone.0106601
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发表时间：
2014-09-11
期刊：
影响因子：
3.7
通讯作者：
Park, David S.
中科院分区：
文献类型：
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作者：
Parsanejad, Mohammad;Bourquard, Noam;Park, David S.
DJ-1（PARK 7）基因的功能缺失突变约占所有家族性帕金森病（PD）的1%。虽然其生理功能尚不完全清楚，但DJ-1在PD的体外和体内模型中保护神经元免受氧化应激。DJ-1抑制氧化应激介导的损伤的分子机制仍然难以捉摸。在这项研究中，我们确定了对氧磷酶-2（PON 2）作为DJ-1的相互作用靶点。PON 2活性在氧化应激反应中升高，DJ-1对这种反应至关重要。重要的是，我们发现PON 2缺乏使神经元对MPP+（1-甲基-4-苯基吡啶）诱导的氧化应激超敏。相反，PON 2的过度表达在这种死亡范例中保护神经元。有趣的是，PON 2有效地挽救了DJ-1缺陷介导的对氧化应激的超敏反应。总之，我们的数据表明，DJ-1发挥其抗氧化活性的模型，至少部分通过调节PON 2。
Loss-of-function mutations in DJ-1 (PARK7) gene account for about 1% of all familial Parkinson's disease (PD). While its physiological function(s) are not completely clear, DJ-1 protects neurons against oxidative stress in both in vitro and in vivo models of PD. The molecular mechanism(s) through which DJ-1 alleviates oxidative stress-mediated damage remains elusive. In this study, we identified Paraoxonase-2 (PON2) as an interacting target of DJ-1. PON2 activity is elevated in response to oxidative stress and DJ-1 is crucial for this response. Importantly, we showed that PON2 deficiency hypersensitizes neurons to oxidative stress induced by MPP+ (1-methyl-4-phenylpyridinium). Conversely, over-expression of PON2 protects neurons in this death paradigm. Interestingly, PON2 effectively rescues DJ-1 deficiency-mediated hypersensitivity to oxidative stress. Taken together, our data suggest a model by which DJ-1 exerts its antioxidant activities, at least partly through regulation of PON2.