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蛋白又被鉴定为家族性帕金森病的致病基因Park7。我们发现，DJ-1反式激活了多巴胺生物合成的关键酶，与多巴胺转运体VMAT-2特异性结合，通过特异性结合和抑制PTEN反式激活依赖于Nrf2的抗氧化应激基因，并与肌动蛋白结合蛋白Drebrin协同作用，是形成神经突起所必需的。在药物开发方面，几种与DJ-1特异结合的小分子化学物质抑制了蛋白质的过氧化，并在氧化应激条件下保存了DJ-1的各种生理活性。因此，这些化学物质被认为是帕金森氏病预防和治疗药物的有前途的候选药物。

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.