Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan.
J Neurochem. 2010 May;113(4):860-70. doi: 10.1111/j.1471-4159.2010.06658.x. Epub 2010 Feb 25.
Mutations in Cu/Zn superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), which could be attributed to the toxic properties of the misfolded protein, oxidative stress, and mitochondrial dysfunction. DJ-1 - a causative agent of familial Parkinson's disease PARK7 - is responsible for inducing antioxidative reaction. In this study, we showed the up-regulation of DJ-1 protein levels in mutant SOD1 transgenic mice through the lifespan were observed in the motor neurons. We demonstrated biochemically DJ-1 formed complexes with mutant SOD1 in the cell lysates. Furthermore, DJ-1 over-expression resulted in increased cell viability and reduced cell toxicity in mutant SOD1-transfected neuronal cells, because of improvement in apoptotic pathway and reduction in oxidative stress levels. We also evaluated DJ-1 levels in CSF collected from sporadic ALS patients and controls subjects. The CSF DJ-1 levels were significantly higher in patients with sporadic ALS than in control subjects. These results show that DJ-1 may be associated with sporadic and familial ALS pathogenesis. Therefore, insight into the effects of DJ-1 on mutant SOD1-mediated toxicity may provide a therapeutic advance for the treatment of motor neuron degeneration in ALS.
铜/锌超氧化物歧化酶（SOD1）基因突变导致家族性肌萎缩侧索硬化症（ALS），这可能归因于错误折叠蛋白的毒性、氧化应激和线粒体功能障碍。DJ-1——家族性帕金森病 PARK7 的致病因子——负责诱导抗氧化反应。在这项研究中，我们通过在运动神经元中观察到突变型 SOD1 转基因小鼠的寿命，显示 DJ-1 蛋白水平上调。我们从生物化学上证明 DJ-1 在细胞裂解物中与突变型 SOD1 形成复合物。此外，由于改善了凋亡途径和降低了氧化应激水平，DJ-1 的过表达导致突变型 SOD1 转染的神经元细胞活力增加和细胞毒性降低。我们还评估了从散发性 ALS 患者和对照受试者中收集的 CSF 中的 DJ-1 水平。散发性 ALS 患者的 CSF DJ-1 水平明显高于对照组。这些结果表明 DJ-1 可能与散发性和家族性 ALS 的发病机制有关。因此，深入了解 DJ-1 对突变型 SOD1 介导的毒性的影响可能为 ALS 中运动神经元退化的治疗提供治疗进展。
