G蛋白偶联雌激素受体调控alpha-synuclein清除参与帕金森病的机制研究

G protein-coupled estrogen receptor 1 (GPER) has been implicated in both rapid signaling and transcriptional regulation of estrogens. Researchers investigate GPER receptor as possible new drug target for neurodegeneration in Parkinson’s disease (PD). We also found that GPER activation protects dopaminergic neurons from MPTP toxicity. Especially, we further discovered that GPER activation improved the clearance of α-synucelin (α-Syn) in astroglial cell culture. Considering accumulation of misfolded α-Syn is a central hallmark of PD, we suppose that the clearance of α-Syn may a mechanism of preventive effect of GPER on PD. Here, using MPTP/p PD chronic model and α-Syn transgenic mice, we will first confirm the role of GPER in the progressive and chronic neurodegeneration of PD, and study the cellular mechanism of GPER underlying the clearance of α-Syn. These findings will demonstrate that GPER regulates the clearance of abnormal protein α-Syn in PD.

G蛋白偶联雌激素受体（GPER）是一类新型雌激素受体。已有文献和我们的前期研究结果均表明，激动GPER对帕金森病（Parkinson’s disease, PD）具有神经保护作用，但其具体机制尚不明确。申请者研究发现，激活GPER能增强星形胶质细胞对α-Syn摄取和清除能力，而α-Syn的异常聚集和传播被认为是PD慢性病理机制的核心。因此，申请者提出：GPER通过促进α-Syn的清除、发挥对PD神经损伤的保护作用。本项目拟制备MPTP慢性病理模型，应用α-Syn转基因小鼠，首先明确GPER对PD慢性病理进程的影响，并进一步研究阐明GPER清除α-Syn的机制及其在PD病理进程中的作用，为发展基于α-Syn清除的新型抗PD药物提供新靶标。