SNARE蛋白在孤独症谱系障碍中的作用机制

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with high disability rate and disease burden. The etiology of ASD is unknown, and the defects in synaptic development and function is one of the major pathogenic hypotheses. SNARE protein complex is the core component of syanpatic vesicle exocytosis process, which is closely related to neurotransmitter transmission. Our previous study found that Syntaxin and NSF, major compositions of SNARE protein complex, were increased in the postmortem brain of ASD patients, which suggested that the SNARE protein complex may be involved in the pathogenesis of ASD. Based on the preliminary work, the present project plans to analyze the association between the expression level of SNARE proteins and ASD, screen the mutation of genes encoding SNARE protein complex and its regulators, and analyze the association between pathogenic variation and ASD in vitro. Through systematic research covering gene and cell, the study aims to explore the pathological mechanism underlying ASD induced by SNARE related genes, and provide reference for clinical diagnosis and medical intervention target of ASD.

孤独症谱系障碍（autism spectrum disorder，ASD）是一组高致残率、高疾病负担的神经发育障碍，目前病因未明，突触发育和功能缺陷是重要的病理机制假说之一，SNARE复合物是突触前囊泡胞吐过程的核心成分，与神经递质的传递密切相关。课题组前期研究发现ASD患者尸脑组织中SNARE复合物中的两个重要蛋白Syntaxin和NSF表达上升，提示SNARE复合物可能参与ASD的病理机制。在前期的工作基础上，本项目拟分析ASD患者尸脑组织SNARE相关蛋白的表达水平与ASD发生的相关性，筛查ASD患者中编码SNARE及其调控因子的相关基因的突变，并通过体外实验分析SNARE相关蛋白和基因与ASD发生的相关性，从基因和细胞层面进行系统性研究，揭示SNARE相关基因导致ASD发生的病理机制，从而为ASD的临床诊断和药物干预靶点提供依据。

孤独症谱系障碍（autism spectrum disorder，ASD）是一组高致残率、高疾病负担的神经发育障碍，目前病因未明，突触发育和功能缺陷是重要的病理机制假说之一，SNARE复合物是突触前囊泡胞吐过程的核心成分，与神经递质的传递密切相关。本课题组在前期ASD患者尸脑组织研究发现SNARE复合物蛋白表达异常的基础上，通过全外显子测序（whole exome sequencing, WES）、Sanger测序等基因组学研究方法筛查ASD患者中编码SNARE及其调控因子的相关基因的突变，在ASD患者及家属中发现了SNARE复合物相关基因的罕见变异（CHD8，SYNE1，SYNE2，CTNND2, NRXN1, MECP2, NRCAM，CNTNAP2等基因），并通过体外细胞实验分析CNTNAP2，MECEP2等基因突变体在神经发育发展中的作用，提示了SNARE相关基因在ASD发生发展中的作用，为ASD的临床诊断和药物干预靶点提供依据。