METH致α-突触核蛋白异常聚集的分子机制及其对氧化应激等神经毒性作用的影响

在研基金项目（No. 81072506）研究结果证明α-SN在METH所致的氧化应激、线粒体功能损害等神经毒性作用中具有关键作用，查阅文献推测该蛋白的异常聚集是其发挥毒性作用的重要形式，为了阐明α-突触核蛋白异常聚集的分子机制，证明其毒性作用，本研究拟通过体内外实验，用分子生物学、神经生物学、分子病理学等技术，并通过特异性抑制剂研究METH作用后α-SN的磷酸化、硝基化和SUMO化修饰对其寡聚体形成的影响作用，探讨对METH神经毒性作用的影响；在转录和翻译水平上观察UPP中Parkin、CHIP和UCH- L1的表达情况，并通过调控上述因子的表达，研究对α-SN的异常聚集的关键作用并探讨对氧化应激等神经毒性作用的影响，进一步阐明METH作用后α-SN是否通过异常聚集发挥其毒性作用，为法医病理诊断和寻找药物靶点奠定良好基础。

The results from the previous fund supported by NSCF (No.81072506) had verified that a-SN played key roles in the neurotoxicity such as oxide stress and damage of mitochondria by METH and literature data suggested that abnormal accumulation of a-SN would be contributed to its function of toxicity. So, we proposed a hypothesis that abnormal accumulation of a-SN would lead to neurotoxicity after METH-treatment. To explore the molecular mechanism and its functions of neurotoxicity, in vitro and in vivo methods and technologies including molecular biology, neural biology and molecular pathology will be used to study the effect on formation of a-SN oligomer after a-SN phosphorylation, nitration and SUMO by METH. The expression of Parkin, CHIP and UCH-L1 during UPP will be detected in the transcription and translation level and modulation of these factors expression will be evaluated for roles of a-SN accumulation which contribute to neurotoxicity of oxide stress. The aims of this study are to elucidate the functions on neurotoxicity of a-SN abnormal accumulation and provide foundation for looking for a new target for forensic medical diagnosis and new drug for patient with METH.