Perry syndrome（PS）由囊泡运输关键蛋白p150glued的功能缺失型突变引起。迄今对于PS中黑质多巴胺能神经元功能异常、变性死亡的发生机制仍知之甚少。前期我们创建了中脑多巴胺能神经元选择性表达功能缺失型p150glued的条件敲除小鼠，发现小鼠纹状体多巴胺转运体DAT功能和含量下降、且表现出早发的运动功能障碍和迟发的多巴胺能神经元变性。我们推测p150glued通过影响囊泡运输干预DAT的合成或降解，从而调控DAT含量，导致多巴胺能神经元功能异常和变性死亡。我们将以小鼠模型和原代神经元为实验对象，使用行为学、病理学、体视学、FSCV、HPLC、细胞生物学和分子生物学技术，从动物整体、组织、细胞、分子等水平，研究p150glued在运动功能障碍、多巴胺能神经元功能异常和变性死亡中的重要作用，阐明p150glued调控DAT合成、降解的亚细胞和分子机制，为PS的防治提供新思路。

Perry syndrome (PS) is a special type of Parkinsonism, caused by loss-of-function mutations of p150glued which plays a key role in dynein/dynactin-mediated vesicular transport. The mechanisms responsible for the dysfunction and degeneration of substantia nigra (SN) dopaminergic neurons in PS patients remain poorly understood. In our previous work we generated a p150glued conditional knockout (p150 cKO) mouse model in which midbrain dopaminergic neurons only express loss-of-function isoforms of p150glued. Our preliminary study showed that loss-of-function of p150glued reduced the function and content of dopamine transporter (DAT) in striatum, and caused early-onset movement disorder and late-onset degeneration of SN dopaminergic neurons in p150 cKO mice. We hypothesize that p150glued changes the stable level of DAT by affecting the synthesis or degradation of DAT through regulating vesicular transport, and thus modulates the function and degeneration of dopaminergic neurons. We will work on p150 cKO mice and cultured primary midbrain neurons by using behavioral tests, pathology, stereology, fast-scan cyclic voltammetry (FSCV), high performance liquid chromatography (HPLC), cell biology and molecular biology techniques, and carry out the project at the individual animal, tissue, cellular and molecular level. We will investigate the important role of p150glued in movement disorder, dysfunction and degeneration of SN dopaminergic neurons, and clarify the sub-cellular and molecular mechanisms how p150glued regulates the synthesis and degradation of DAT. The results of our study will provide new ideas for the treatment of PS patients.