Parsanejad Mohammad, Bourquard Noam, Qu Dianbo, Zhang Yi, Huang En, Rousseaux Maxime W C, Aleyasin Hossein, Irrcher Isabella, Callaghan Steve, Vaillant Dominique C, Kim Raymond H, Slack Ruth S, Mak Tak W, Reddy Srinivasa T, Figeys Daniel, Park David S
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Department of Medicine and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at Univeristy of California Los Angeles, Los Angeles, California, United States of America.
PLoS One. 2014 Sep 11;9(9):e106601. doi: 10.1371/journal.pone.0106601. eCollection 2014.
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.
DJ-1（PARK7）基因的功能丧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，但在PD的体外和体内模型中，DJ-1均可保护神经元免受氧化应激。DJ-1减轻氧化应激介导损伤的分子机制仍不清楚。在本研究中，我们鉴定出对氧磷酶-2（PON2）是DJ-1的相互作用靶点。PON2活性在氧化应激反应中升高，而DJ-1对这一反应至关重要。重要的是，我们发现PON2缺乏会使神经元对MPP+（1-甲基-4-苯基吡啶鎓）诱导的氧化应激高度敏感。相反，PON2的过表达在这种死亡模式下可保护神经元。有趣的是，PON2可有效挽救DJ-1缺乏介导的对氧化应激的高度敏感性。综上所述，我们的数据提示了一种模型，即DJ-1至少部分通过调节PON2发挥其抗氧化活性。
