线粒体膜电位相关蛋白VDAC在A53T α-突触核蛋白致神经损伤中的作用及其机制研究

Parkinson disease(PD) is a common degenerative disorder of the central nervous system in the elderly. Which has a high prevalence and morbidity. The A53T mutation of alpha-synuclein (a-syn) has been proven to be a critical factor in causing PD, but the mechanism has yet to be fully elucidated. Recent studies have shown that loss of mitochondrial membrane potential play the key role in pathogenic process of PD. Our pilot experiments demonstrated that A53T mutant a-syn upregulated voltage-dependent anion channel(VDAC) protein expression and phosphonation，inducing mitochondrial membrane potential collapse, and subsequent neuronal damage. Base on the preliminary study, we plan to use transgenic animal models and cell models, utilize molecular biology, proteomics and behavioral methods to study the effect and the molecular mechanisms of A53T a-syn on VDAC regulation，expound the key role of VDAC in neuronal damage and PD, and thus provide new clues for the PD pathogenesis and therapeutic intervention.

帕金森病（PD）是中老年人常见的中枢神经系统变性疾病，患病率和致残率均较高。Alpha-突触核蛋白（a-syn）的A53T基因突变已证实是PD的经典致病因素，然而其具体作用途径仍在探索之中。最近研究表明，线粒体膜电位失衡是PD发病的关键环节。我们的前期实验显示A53T a-syn促使线粒体膜电位相关蛋白VDAC表达上调，磷酸化活性增强，导致线粒体膜电位失衡，并由此引起线粒体功能障碍和神经元损伤。在此基础上，本项目拟利用转基因动物模型和细胞模型，综合分子生物学、蛋白质组学、行为学等方法，研究A53T a-syn对VDAC的影响及其具体分子机制，明确VDAC在A53T a-syn致神经损伤和PD发病中的关键作用，并由此为PD发病机制研究及干预治疗提供新的线索。

帕金森病（PD）是中老年人常见的中枢神经系统变性疾病。Alpha-突触核蛋白（a-syn）的A53T基因突变已证实是PD的经典致病因素。本项目明确了A53Tα-Syn通过作用于线粒体膜电位相关蛋白VDAC导致神经元线粒体膜电位水平下降；VDAC对A53Tα-Syn导致的线粒体膜电位失衡具有调控作用；干预VDAC可影响A53Tα-Syn导致的线粒体膜电位失衡、线粒体形态和功能异常以及神经元活性改变；A53T α-Syn对线粒体膜通道蛋白VDAC磷酸化活性调节的作用；GSK-3β信号蛋白是介导A53T α-Syn对线粒体膜通道蛋白VDAC磷酸化活性调节，进而引起线粒体膜电位失衡和功能损伤的的关键信号蛋白；VDAC1磷酸化亚型是A53T α-Syn 致病过程中GSK-3β调控VDAC活性的关键因素。结果表明靶向P-VDAC1 siRNA对A53Tα-Syn致线粒体膜电位失衡和线粒体功能损害的保护作用及其信号通路机制，为进一步帕金森病干预治疗及寻找药物靶点提供了依据。