Pathogenic mechanisms of Parkinson's disease via DJ-1 and targeted drug development

通过对原癌基因DJ-1的产物DJ-1蛋白的功能分析，分析了帕金森病发病的分子机制，DJ-1蛋白也被鉴定为PARK 7，是家族性帕金森病的责任基因。我们发现，DJ-1反式激活多巴胺生物合成的关键酶，特异性结合到多巴胺转运蛋白VMAT-2，通过特异性结合和抑制PTEN反式激活Nrf 2依赖性抗氧化应激基因，并需要与肌动蛋白结合蛋白Drelene合作形成神经突。至于药物开发，几种与DJ-1特异性结合的低分子化学物质阻止了蛋白质的过度氧化，并在氧化应激条件下保留了DJ-1的各种生理活性。这些化合物有望成为帕金森病的预防和治疗药物。

Molecular mechanisms of Parkinson’s disease pathogenesis were analyzed by functional analyses of DJ-1 protein, the product of protooncogene DJ-1, also identified as PARK7, a responsible gene for familial Parkinson’s disease. We revealed that DJ-1 transactivated key enzymes for dopamine biosynthesis, specifically bound to a dopamine transporter VMAT-2, transactivation of Nrf2-dependent anti-oxidative stress genes via specific binding and inhibition of PTEN, and was required for neurite formation in cooperation with Drebrin, an actin-binding protein. As for drug development, several low-molecular chemicals specifically bound to DJ-1 prohibited hyperoxidation of the protein and preserved a variety of physiological activities of DJ-1 under oxidative stress conditions. The chemicals were thus suggested to be promising candidates for preventive and curative drug for Parkinson’s disease.