PPT1介导RalA棕榈酰化修饰调控树突棘发育的分子机制

树突棘的正常发育是神经网络形成的物质基础，其异常将导致多种神经疾病的发生。动态的蛋白棕榈酰化修饰在树突棘的发育过程中起着重要的调控作用，去棕榈酰化酶PPT1的缺失导致了严重的神经退行性疾病。研究指出PPT1敲除小鼠中神经元树突棘的种类和密度明显异常，此病理表型是否与PPT1的缺失直接相关目前并不明确。申请人利用PPT1功能缺失模型鼠（PPT1-KI）结合棕榈酰化蛋白组学技术发现PPT1缺失后RalA的棕榈酰化修饰水平明显上调；同时，我们的初步研究指出RalA促进树突棘的发育可能依赖于其蛋白的棕榈酰化修饰水平。据此，我们假设PPT1可能通过调节RalA的棕榈酰化修饰水平进而调控树突棘的发育。本项目的深入开展将阐明PPT1介导RalA棕榈酰化修饰水平的变化与树突棘发育异常的分子调控机制，为相关神经退行性疾病的诊断和治疗提供新的思路。

The proper development of dendritic spines is the structural basis of functional neural circuits, the abnormality of which would cause severe neurological diseases. As dynamic palmitoylation plays important roles in regulating the formation of dendritic spines, the loss function of PPT1 (an enzyme that catalyze the depalmitoylation process) results in serious neurodegenerative disease both in human and in mice. Previous studies pointed out that the density as well as the morphological subtypes of dendritic spines are apparently altered in PPT1-deficient mice, yet, if such pathological phenotype a direct consequence of the loss of PPT1 remains not fully understood. Applying the approach of palm-proteomics, we found that RalA palmitoylation is dramatically upregulated in PPT1-deficient mice; meanwhile, our prelimilary data also indicate that palmitoylation is essential for RalA to exert its function in enhancing the formation of dendritic spines. On these basis, we hypothesized that PPT1 might regulate the development of dendritic spines by manipulating the level of RalA palmitoylation. Future works would extend our understanding that how altered level of RalA palmitoylation is involved in controlling the abnormal development of dendritic spines in PPT1-deficient mice, which would, in turn, provide novel strategic resolutions for the diagnosis and treatment of neurodegenerative diseases.