Egr-1在帕金森病多巴胺能神经元死亡中的作用及其机制研究

帕金森病(PD)发病的本质是黑质多巴胺(DA)能神经元死亡，其具体机制尚未阐明。我们在细胞模型中已证明：转录因子Egr-1直接激活促凋亡蛋白Bim表达导致神经元凋亡；干扰Egr-1或用mithramycin A抑制Egr-1转录活性均保护神经元(J Neurosci 2011)。最近，我们在PD小鼠模型发现，黑质DA神经元Egr-1表达上调；给予mithramycin A保护性干预了DA神经元死亡，提示Egr-1介导DA神经元死亡。进一步发现Bim在PD小鼠DA神经元中上调；JNK、GSK-3均可能介导Egr-1/Bim的上调。据此我们提出假设：JNK或(和)GSK-3激活并上调Egr-1，后者转录激活Bim，最终导致DA神经元死亡/PD发生。本项目拟采用基因工程小鼠、腺相关病毒、激酶抑制剂等工具，阐明Egr-1在DA神经元死亡中的关键作用及其调控机制，为寻找神经保护治疗靶点提供科学依据。

Parkinson disease (PD) results primarily from the death of dopaminergic neurons in the substantia nigra, the pathogenesis of which is not completely understood. We have observed that the transcription factor Egr-1 was upregulated during neuronal death. Both Egr-1 knock-down and suppression of Egr-1 activity by mithramycin A were neuroprotective and Bim was its direct target gene (J Neurosci 2011). Here we show for the first time that Egr-1 expression increased within dopaminergic neurons in a mouse model of PD. Mithramycin A had neuroprotective effects. These data suggest that Egr-1 might play an important role in dopaminergic neuron death. Moreover, we showed increased Bim expression in dopaminergic neurons in situ right after Egr-1 upregulation. Both JNK and GSK-3, key players in determining neuronal cell fate, may be involved in this process. Putting these observations together, we propose that upregulation of Egr-1 mediated by JNK or (and) GSK-3 leads to Bim transactivation and ultimately dopaminergic neuron death. We propose to clarify the critical role of Egr-1 in dopaminergic neuron death and the underlying mechanism(s) by genetically engineered mice, adeno-associated virus, kinase inhibitors and so on, in order to provide scientific evidence for establishment of therapeutic target for PD.