自闭症是中枢神经系统发育障碍性疾病，可伴有神经元轴突分支异常。我们新近在自闭症患者中发现新发MARK2基因移码突变，造成该蛋白C末端缺失；相应位点突变大鼠表现出明显的自闭症样行为；进一步实验发现MARK2此突变可引起神经元轴突分支增多，且SNPH蛋白Ser20位点磷酸化显著下调。基于SNPH蛋白可通过调控线粒体的动态分布影响轴突分支，我们推测SNPH Ser20磷酸化下调是MARK2此突变引起轴突分支增多的分子基础。本课题拟：1）验证SNPH Ser20磷酸化下调可介导MARK2此突变引起的轴突分支增多；2）检测SNPH Ser20磷酸化下调对线粒体动态分布的影响明确其调控轴突分支的途径；3）探究MARK2此突变引起SNPH Ser20磷酸化下调及其影响线粒体动态分布的具体分子机制。所得结果将揭示MARK2 C末端缺失引起轴突分支增多的作用机制，为寻找自闭症治疗靶点提供新思路。

Autism is severe neurodevelopmental disorders. Abnormal axon branches of neurons was significantly correlated with autism. We recently found a novel frameshift mutation of MARK2 gene in autistic patients, resulting in the C terminal deletion of this protein; The rats with the corresponding mutation showed obvious autistic-like behavior; Further experiments found that the MARK2 mutation could lead to an increase in axon branches, moreover, the phosphorylation of SNPH protein at serine 20 was down-regulated. Studies have shown that SNPH proteins can affect axonal branches by regulating the dynamic distribution of mitochondria, We speculate that the phosphorylation of SNPH Ser20 is the molecular basis for the increase in axon branching caused by MARK2 mutation. This study will: 1) verify that phosphorylation of SNPH Ser20 can mediate the increase of axon branches caused by MARK2 mutation; 2) detect the influence of SNPH Ser20 phosphorylation downregulation on the dynamic distribution of mitochondria and identify the pathways through which it regulates axon branches; 3) reveal the mechanism of MARK2 mutation causing the reduction of SNPH Ser20 phosphorylation and its influence on mitochondrial distribution. This study will reveal the mechanism of increased axonal branches caused by the loss of MARK2 C terminal, and provide new ideas for finding the therapeutic target of autism.