帕金森病（PD）的发病本质是中脑黑质多巴胺（DA）神经元死亡，目前尚无有效的神经保护手段。神经炎症是DA神经元进行性死亡的重要原因。我们和其他实验室已证明JNK是介导DA神经元死亡的关键激酶。我们在PD小鼠模型中进一步发现：JNK主要在DA神经元内激活；JNK三个亚型（JNK1、JNK2、JNK3）分别全身敲除均抑制黑质局部神经炎症发生；JNK下游转录因子ATF2介导DA神经元死亡（Exp Neurol 2016第一作者）但不调控神经炎症。那么，关键问题是：是否DA神经元内的JNK介导神经炎症发生？哪个JNK亚型起关键作用？此过程是否下游转录因子c-Jun依赖、通过转录上调MMP3所介导？本项目拟采用DA神经元选择性的JNK各亚型及c-Jun基因敲除小鼠进行研究以回答这些问题，为阐明JNK介导神经炎症的机制、解析DA神经元损伤/死亡与神经炎症的关系、确立JNK为PD治疗靶标提供科学依据。

Parkinson’s disease (PD) is a common neurodegenerative disease whose cardinal symptoms are due to the progressive loss of dopamine neurons of the substantia nigra. A crucial goal of PD-related research is the development of a neuroprotective treatment that delays disease progression. It has been established that JNK is a critical regulator of dopamine neuron death in PD by us and others. Further, we found in a mouse model of PD: i) JNK is activated predominantly and earliest in dopamine neurons; ii) dopaminergic neurotoxin-induced neuroinflammation is blocked in global JNK1-, JNK2- or JNK3-knockout mice; iii) JNK2/3-mediated activation of ATF2 contributes to dopaminergic neurodegeneration while functional loss of ATF2 in dopamine neurons has no effect on neuroinflammation. We hypothesize that JNKs of dopamine neurons play a role in neuroinflammation and mediate dopaminergic neurodegeneration via a non-cell-autonomous mechanism. We propose to clarify whether it is the JNKs of dopamine neurons and which isoform(s) are involved in neuroinflammation; whether JNKs-mediating neuroinflammation is c-Jun-dependent; whether Mmp3 is the downstream target of JNK/c-Jun to induce neuroinflammaiton, by using dopamine neuron-specific JNK1-，JNK2-, JNK3- or c-Jun-knockout mice. This proposal will provide scientific evidence of elucidation of the mechanism of JNKs-mediated neuroinflammaiton and establishment of JNK as the target for neuroprotective therapy for PD.