SEPW1对巨自噬的调控作用及其对帕金森病发病的影响

巨自噬-溶酶体途径所介导的蛋白降解紊乱是帕金森病（PD）发病的主要机制之一。氧化应激被认为是巨自噬功能发生紊乱的重要因素，但是这之间信号是如何传递的并不完全清楚。机体氧化还原蛋白的代偿性改变可能与此有关。课题组发现硒氧还蛋白SEPW1在黑质中有高表达且在PD模型和患者外周血中水平升高。SEPW1可受氧化应激诱导，能够影响神经细胞巨自噬活性，但不参与线粒体自噬的调控，不影响凋亡，进一步分析提示SEPW1可调控自噬小体的形成。结合初步机制分析，课题组提出，SEPW1是PD中氧化应激干扰巨自噬功能的一个中间节点，其表达增强可通过AMPK和/或14-3-3蛋白介导的途径，抑制神经元自噬小体的生成，进而导致α-synuclein等蛋白降解异常，促进PD的发病。本项目拟在细胞、转基因动物和外周血细胞中就上述假说展开深入探索。研究成果对认识PD的发病机制、发现潜在干预靶点和诊断指标具有新的重要意义。

Macroautophagy-lysosome pathway-mediated dysfunction of protein degradation is one of the major mechanisms underlying pathogenesis of Parkinson’s disease (PD). Oxidative stress is considered as an important factor contributing to the dysfunction of macroautophagy. However, how the signal transduced from oxidative stress to macroautophagy dysfunction is not completely understood. The compensatory responses of redox proteins may be associated in this case. We found that redox selenoprotein SEPW1 was highly expressed in the substantia nigra and was elevated in PD models and peripheral blood of patients. SEPW1 was inducible by oxidative stress, displayed an impact on the activity of macroautophagy but not that of mitochondrial autophagy and had no effect on neuronal cell apoptosis. Analysis further suggested that SEPW1 modulated the formation of autophagosome. In combination with preliminary mechanism analyses, we herein proposed that: SEPW1 is a middle connector of oxidative stress disturbing the function of macroautophagy in PD. Increased expression of SEPW1 inhibits the formation of autophagosome in neuronal cells via AMPK and/or 14-3-3 mediated pathways, leads to abnormal degradation of α-synuclein and other proteins, and thereby promotes the pathogenesis of PD. The current project aims to thoroughly investigate the above hypothesis in cells, transgenic mice and peripheral blood cells. Our findings provide novel and important insights into the understanding of PD pathogenic mechanisms and the development of intervention targets and diagnostic markers.