细胞自噬在清除错误折叠蛋白形成的毒性聚集体过程中发挥重要作用，与神经退行性疾病发生发展密切相关。申请人在前期大规模自噬新关键基因筛选基础上，初步发现蛋白质S-棕榈酰化这种新型修饰对于自噬通路的关键作用。S-棕榈酰化新型修饰对自噬重要性和机制的阐明将推动对自噬调控的深入认识。申请人将利用蛋白复合物纯化方法、酰基-生物素置换法等化学生物学方法和分子生物学方法来检测分析这种新型修饰与自噬的关系。进一步将从这种新型修饰的自噬生物学效应和动态调控规律来深入揭示其在自噬中的功能和机制。这将为后续基于新型修饰进行化学干预神经退行性疾病提供潜在靶点分子和药物筛选策略。

Autophagy pathway mediated clearance of toxic protein aggregates is pivotal for cellular homeostasis. The link between autophagy and neurodegeneration is well established. In previous high throughput screening for autophagy genes, the applicant found one novel type of modification, S-palmitoylation, is suggested to be involved in autophagy process. After confirmation the function of this type of modification in autophagy, the applicant plans to use molecular and chemical methods like unnatural amino acid photochemical-click chemical probes into the intact enzyme-substrate complex, Acyl-biotinyl exchange to clarify the according catalytic enzyme. The detailed illumination for the function and mechanism of this novel type of modification in autophagy will provide promising potential targets for future drug development in neurodegeneration diseases.