基于PINK1/Parkin通路调节线粒体自噬探讨归脾汤改善MMA认知障碍的作用机制

MMA是我国罕见病中最常见的遗传代谢病，认知障碍是其最主要的并发症，严重影响患儿的生存质量，至今尚无有效疗法。MMA认知障碍与海马神经元氧化应激损伤密切相关，MMA细胞中线粒体自噬过程受阻是海马神经元氧化应激损伤的重要原因。归脾汤治疗MMA认知障碍疗效确切。基础研究显示，归脾汤可通过减轻细胞氧化应激损伤发挥治疗作用。PINK1/Parkin通路参与调控线粒体自噬，可能是MMA海马神经元氧化应激损伤发生的关键环节。由此我们提出归脾汤可能通过PINK1/Parkin通路调控线粒体自噬，减轻海马神经元损伤，改善MMA认知障碍这一科学假说。本课题将从体内和体外两方面，利用siRNA沉默和过表达PINK1，检测下游关键蛋白的表达，线粒体自噬相关分子，氧化应激指标，阐明该通路在MMA认知障碍中的作用，并揭示归脾汤的疗效机制。为探索中医药防治MMA认知障碍提供科学依据。

MMA is the most common genetic metabolic disease in rare diseases in China. Cognitive impairment is the main complication of MMA, which seriously affects the quality of life of children. So far, there is no effective treatment. Cognitive impairment of MMA is closely related to oxidative stress injury of hippocampal neurons. The inhibition of mitochondrial autophagy in MMA cells is an important reason for oxidative stress injury of hippocampal neurons. Guipi Decoction is effective in treating cognitive impairment of MMA. Basic research shows that Guipi Decoction can play a therapeutic role by reducing oxidative stress injury of cells. Pink1/Parkin pathway is involved in the regulation of mitochondrial autophagy, which may be a key link in the oxidative stress injury of MMA hippocampal neurons. Therefore, we propose that Guipi Decoction may regulate mitochondrial autophagy through Pink1/Parkin pathway, alleviate hippocampal neuron damage and improve MMA cognitive impairment. In this project, we will use siRNA to silence and overexpress Pink1 in vivo and in vitro to detect the expression of downstream key proteins, mitochondrial autophagy related molecules, oxidative stress indicators, clarify the role of this pathway in MMA cognitive impairment, and reveal the therapeutic mechanism of Guipi Decoction. Objective to provide scientific basis for the prevention and treatment of MMA cognitive impairment with traditional Chinese medicine.