中脑黑质多巴胺能神经元大量丢失是帕金森氏病（PD）最重要的病理基础，多种环境毒素和遗传因素可引发黑质神经元特异性死亡；近年研究发现，坏死和凋亡之外的新型死亡途径——细胞焦亡（Pyroptosis）参与多种疾病发生发展，但其在PD中的作用机理尚待证实。本项目遵循转化医学理念，首先在细胞—组织—动物—临床PD样品中验证NLRP3炎症小体激活介导的神经元焦亡在PD发病中的关键作用，检测脑脊液IL-1β、IL-18可否作为PD诊断指标；进而深入研究PD神经元炎症小体激活分子机制，探讨神经系统关键激酶Cdk5是否可以磷酸化Sirt2，下调其去乙酰化酶活性导致微管蛋白α-tubulin过度乙酰化，通过促进微管转运，引发NLRP3炎症小体组装和激活，诱发IL-1β、IL18释放和神经元焦亡；最后验证干预Cdk5磷酸化Sirt2可否保护PD神经元细胞焦亡，为PD神经元死亡的机制研究提供新思路和治疗靶点。

The substantial loss of dopaminergic neurons in substantia nigra is the most important pathological basis of Parkinson's disease (PD), a variety of environmental toxins and genetic factors can lead to specific neuronal cell death in the substantia nigra. Recent studies have found that, in addition to the classic form of cell death, necrosis and apoptosis, a new type of programmed cell death, caspase-1-dependent pyroptosis were proved. Pyroptosis are confirmed to participate in the progression of infectious diseases and atherosclerosis, but whether pyroptosis is involved in neuronal death in PD, and its mechanism has yet to be confirmed. The current project follows the concept of translational medicine. Firstly, we evaluate the key role of caspase-1-dependent NLRP3 inflammasome activation and neuronal pyroptosis in the cellular models, animal models and clinical specimens of Parkinson's disease. Thus, we deeply explore the molecular mechanisms of the neuronal inflammasome activation, and we focus on the phosphorylation of deacetylase Sirtuin-2 by Cdk5, one of the critical kinase in nervous system, which lower the deacetylase activity of Sirtuin-2, resulting in excessive acetylation of α-tubulin, and consequent NLRP3 inflammasome activation and neuronal pyroptosis. Finally, we verify whether the intervention of Cdk5 phosphorylation Sirt2 could have protective effects of neuronal cell death in PD models. This project focus on the provision of new research ideas and therapeutic targets for dopaminergic neuronal death in PD.