Wnt通路参与星形胶质细胞对多巴胺神经元保护作用的机制研究

Neuroprotection deficiency of astrocytes on dopaminergic neurons was considered as an important cause of Parkinson’s disease. The Wnt signaling pathway is an autocrine paracrine signal transduction pathway which has been demonstrated to participate in many physiological and pathophysiological procedures. The Wnt signal in brain mainly originates from astrocytes and plays key roles in the expression, secretion and reuptake of neurotransmitters and cytokines. However, the function of Wnt signal in astrocytes, especially in PD, is really far from clear. Our previous study shows that the Wnt/β-catenin pathway in PD model is inhibited while exogenous Wnt signal displays protective effects on DA neurons. Based on the previous work, the applicant proposed that Wnt signal participant in the protective effect of astrocytes on DA neurons through, for one side, regulating the release of protective factors and the reuptake of excitatory amino acids, for another, binding Frizzled receptors on the DA neurons and regulating anti-apoptosis mechanism. To certify this hypothesis, endogenous or exogenous Wnt signal will be exert in PD models, the functional changes of astrocytes and DA neurons will be detected, and the protective mechanisms of astrocytes on DA neurons will be investigated.

星形胶质细胞保护作用的缺失是帕金森病（PD）多巴胺（DA）神经元凋亡的重要原因，Wnt通路是一条参与机体多种生理过程的旁分泌和自分泌通路，脑内Wnt信号主要源自星形胶质细胞，参与脑内多种递质、因子的表达、分泌和回收。Wnt信号在PD发病中的作用仍然很不清楚。我们前期研究显示PD模型中Wnt/β-catenin信号被抑制，而外源性Wnt信号对DA神经元具有保护作用。结合前期工作，申请者提出Wnt信号参与星形胶质细胞对DA神经元的保护作用，一方面可能调节星形胶质细胞自身保护性因子的分泌、兴奋性氨基酸的摄取，另一方面星形胶质细胞分泌的Wnt蛋白可直接通过Frizzled受体调节DA神经元的抗凋亡机制。为证实本假说，本研究拟采用PD细胞及动物模型，通过对内源性或外源性Wnt信号进行干预并检测星形胶质细胞及DA神经元功能的变化，分析Wnt信号在星形胶质细胞对DA神经元的保护作用。

星形胶质细胞保护作用的缺失是帕金森病（PD）多巴胺（DA）神经元凋亡的重要原因，Wnt通路是一条参与机体多种生理过程的旁分泌和自分泌通路，脑内Wnt信号主要源自星形胶质细胞，参与脑内多种递质的表达。本项目研究显示星形胶质细胞和多巴胺神经元中存在多种Wnt通路相关受体（如Frizzled-1、Frizzled-2）的表达，PD模型中Wnt/β-catenin信号被抑制，通过外源性的Wnt3a、Wnt5a，以及通过与过表达Wnt1的星形胶质细胞共培养，可激活经典Wnt通路，发挥对DA神经元具有保护作用。Wnt信号参与星形胶质细胞对DA神经元的保护作用，一方面通过调节星形胶质细胞自身保护性因子的分泌（如BDNF、GDNF），另一方面星形胶质细胞分泌的Wnt蛋白可直接通过Frizzled受体调节DA神经元的抗凋亡机制，这其中有β-catenin、Akt等抗凋亡信号分子的参与，也有NF-κB介导的兴奋性氨基酸转运体GLT-1的参与。本项目的研究结果为帕金森病的病因研究提供了理论依据，为将来多巴胺神经元的神经保护治疗提供了新的靶点。