α突触核蛋白（α-synucelin, α-Syn）的错误折叠、异常聚集及其在细胞间的传播是帕金森病（Parkinson’s disease, PD）病理机制的核心。目前已发现，脑内星形胶质细胞具有直接清除和吞噬脑内废物的能力。而申请者在既往国家自然科学基金的资助下已阐明水通道蛋白4（Aquaporin-4，AQP4）参与PD的发生发展；进一步发现AQP4敲除引起小鼠中脑α-Syn的表达显著增加，导致星形胶质细胞清除α-Syn的能力下降。因此，申请者提出“AQP4通过调节星形胶质细胞α-Syn的清除能力影响PD的进程”。本项目拟应用AQP4敲除鼠和AQP4-A25Q突变敲入鼠，借助显微成像流式细胞技术和激光共聚焦活细胞观测技术，研究、阐明不同亚型或膜分布特点的AQP4调节星形胶质细胞清除α-Syn的机制及其在PD病理进程中的作用，为发展基于星形胶质细胞的新型抗α-Syn药物提供新靶标。

Formation and accumulation of misfolded α-synucelin (α-Syn) is a central hallmark of Parkinson's disease (PD). Recent studies found that astrocytes are crucial in clearance of abnormal proteins, such as Aβ and α-Syn. We have demonstrates that AQP4 plays an important role in the pathophysiology of PD. Furthermore, we found that AQP4 deficiency induced α-Syn aggregation in midbrain, and reduced the astroglial clearance of α-Syn in cell culture. Thus, we suppose that AQP4 regultes the astroglial clearance of α-Syn, which is involved in the vulnerability of DA neurons to neurodegeneraion. Here, using AQP4 knockout mice and AQP4-A25Q knockin mice, we first determined whether AQP4 regulates the propagate and spread of pathological a-Syn conversion when introduced into mice by stereotaxic injections or transfection. Furthermore, primary astrocyte culture from adult or neonatal mice are used to study the cellular mechanism of AQP4 underlying the clearance of α-Syn. These findings will demonstrate that glial AQP4 regulates the clearance of abnormal protein α-Syn in PD.