Ma Jun, Wu Rong, Zhang Qiang, Wu Jun-bing, Lou Jizhong, Zheng Zheng, Ding Jian-qing, Yuan Zengqiang
*State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
†Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing 100053, China.
Biochem J. 2014 Sep 15;462(3):489-97. doi: 10.1042/BJ20140235.
PD (Parkinson's disease) is a complex disorder that is associated with neuronal loss or dysfunction caused by genetic risks, environmental factors and advanced aging. It has been reported that DJ-1 mutations rendered neurons sensitive to oxidative damage, which led to the onset of familiar PD. However, the molecular mechanism is still unclear. In the present study we show that DJ-1 interacts with RACK1 (receptor of activated C kinase 1) and increases its dimerization and protein stability. The DJ-1 transgene protects cortical neurons from H2O2-induced apoptosis, and this protective effect is abrogated by knocking down RACK1. Similarly, deletion of DJ-1 in cortical neurons increases the sensitivity to H2O2, and the damage can be significantly rescued by DJ-1 or DJ-1/RACK1 co-transfection, but not by RACK1 alone. We observed further that the interaction of DJ-1 and RACK1 is disrupted by H2O2 or MPP+ (1-methyl-4-phenylpyridinium) treatment, and the protein levels of DJ-1 and RACK1 decreased in neurodegenerative disease models. Taken together, the DJ-1-RACK1 complex protects neurons from oxidative stress-induced apoptosis, with the implication that DJ-1 and RACK1 might be novel targets in the treatment of neurodegenerative diseases.
帕金森病（PD）是一种复杂的疾病，与由遗传风险、环境因素和衰老导致的神经元丢失或功能障碍相关。据报道，DJ-1突变使神经元对氧化损伤敏感，从而导致家族性帕金森病的发病。然而，其分子机制仍不清楚。在本研究中，我们发现DJ-1与活化C激酶1受体（RACK1）相互作用，并增加其二聚化和蛋白质稳定性。DJ-1转基因可保护皮质神经元免受过氧化氢诱导的凋亡，而敲低RACK1可消除这种保护作用。同样，皮质神经元中DJ-1的缺失增加了对过氧化氢的敏感性，通过DJ-1或DJ-1/RACK1共转染可显著挽救这种损伤，但单独转染RACK1则无效。我们进一步观察到，过氧化氢或1-甲基-4-苯基吡啶离子（MPP+）处理会破坏DJ-1与RACK1的相互作用，并且在神经退行性疾病模型中DJ-1和RACK1的蛋白质水平会降低。综上所述，DJ-1-RACK1复合物可保护神经元免受氧化应激诱导的凋亡，这意味着DJ-1和RACK1可能是治疗神经退行性疾病的新靶点。
