新自噬基因SAC1对神经退行性疾病的影响及机制研究

神经退行性疾病种类多，发病机制复杂，缺乏有效的诊断及治疗手段，是人口老龄化社会的巨大挑战。大量研究表明自噬是与多种神经退行性疾病相关的新机制。申请人一直从事衰老和自噬相关工作，在酵母及哺乳动物细胞中发现了新的自噬基因SAC1，且SAC1神经元特异敲除小鼠有明显神经退行性疾病表型。SAC1参与果蝇的神经发育调控，但在哺乳动物神经系统中的功能尚未有研究。因此本项目提出，哺乳动物神经元SAC1的敲除可抑制自噬，促进神经退行性病变。本课题拟通过构建SAC1神经元特异敲除小鼠，明确小鼠神经元SAC1的敲除所导致的神经退行性病变表型；然后具体研究该表型内在的病理机制及小鼠神经元中的自噬水平；最后在原代神经元细胞中，通过调控SAC1的底物PI4P浓度进一步研究SAC1导致自噬抑制及神经退行性病变的作用机制。SAC1基因在神经系统的功能研究将为神经退行性疾病发病机制及新药物靶点开发提供新的线索。

Neurodegenerative diseases are great challenges in the accelerating aging society, with complex pathogenesis and lack of effective diagnosis and treatment. Recently, autophagy has been proved to be a novel mechanism involved in a variety of neurodegenerative diseases. The applicant has been engaged in research of aging and autophagy, and found SAC1 is a novel autophagy gene in yeast and mammalian cells. SAC1 has been reported as a phosphatidylinositol phosphatase involved in neurodevelopment of Drosophila melanogaster, while the function of SAC1 in animal nervous system remains elusive. Furthermore, our study showed that SAC1 deficiency would result in a neurodegenerative phenotype. Therefore, we propose that SAC1 deficiency can induce neurodegenerative diseases through autophagy inhibition in neurons. In this study, we constructed neuron-specific SAC1 knockout mice to clarify the phenotype of neurodegenerative disease, the pathological mechanism of this phenotype and the level of autophagy in mouse neurons. Finally, the mechanism of autophagy inhibition and neurodegeneration induced by SAC1 was further studied by regulating the concentration of PI4P, the substrate of SAC1, in primary neurons. The study of SAC1 in the nervous system would provide new clues for the pathogenesis and the new drug targets of neurodegenerative diseases.