m6A甲基转移酶METTL14调控α-突触核蛋白异常聚集的分子机制研究

α-突触核蛋白（α-Syn）异常聚集作为帕金森病发病中的核心环节，其调控机制尚未阐明。近年研究表明m6A修饰在疾病发生发展过程中的重要性日益凸显。我们发现帕金森病患者外周血m6A修饰水平明显下降，m6A甲基转移酶METTL14基因低表达，并与α-Syn呈负相关。进一步的功能实验表明敲低METTL14能够促进α-Syn聚集。m6A测序(MeRIP-seq)结合生物信息分析初步揭示METTL14可能通过自噬溶酶体融合基因STX17调控α-Syn聚集。本项目拟在前期基础上，采用体内/体外模型并结合临床样本，通过基因沉默/过表达、RNA免疫共沉淀等策略，阐明METTL14低表达通过降低STX17的稳定性和翻译效率，进而抑制自噬溶酶体融合，使α-Syn聚集体不能顺利清除，最终加速帕金森病发生发展的详细机制，以期为帕金森病防治提供新的靶点和理论依据。

The mechanisms of α-synuclein in the development of Parkinson’s disease are still largely unknown. Recently studies have suggested that m6A RNA modification plays an important role in the development of several diseases. We identify the expression of serum m6A and m6A methyltransferase METTL14 were significantly lower in PD patients compared to normal controls, correlation analysis revealed METTL14 was negative correlated with serum α-synuclein level. Further in vitro experiments demonstrated that the knock down of METTL14 could promote the aggregation of α-synuclein. Subsequenly MeRIP-Seq has revealed that autophagosome-lysosome gene STX17 may be involved in regulating the aggregation of α-synuclein. Based on the above, this project will use in vivo/in vitro models and clinical samples, as well as gene transfection and RNA co-immunoprecipitation to further verify whether METTL14 deficiency promotes aggregation of α-synuclein through decreasing STX17 mRNA stability and translation efficiency, therafter inhibiting autophagosome-lysosome fusion, and eventually lead to the development of PD. This project will provide new targets for the diagnosis and therapy of PD.