蛋白质磷酸化是调控蛋白质功能最重要的方式，磷酸化失控与很多疾病的发生发展相关。α-突触核蛋白（α-syn）第129位丝氨酸磷酸化（pS129α-syn）可能与帕金森症发生密切相关，然而目前尚不清楚α-syn异常磷酸化的分子机制。细胞内核磁共振是最近发展起来的能在活细胞内获取原子分辨蛋白质动态信息的新技术。本项目将采用细胞内核磁共振方法在神经细胞内研究pS129α-syn的去磷酸化和降解过程，探索神经细胞清除异常磷酸化α-syn的作用机制以及与疾病发生的相关性。具体包括：1.研究神经细胞内α-syn的去磷酸化和降解过程；2.探索神经细胞清除磷酸化α-syn的主要途径；3.研究帕金森症细胞模型是否存在α-syn去磷酸化及降解相关功能障碍。研究结果将在原子水平阐述神经细胞内pS129α-syn的动态变化规律，有助于揭示帕金森症发生发展中α-syn异常磷酸化和神经细胞功能障碍的分子机制。

Protein phosphorylation represents an important regulatory mechanism in cells, and errors in protein phosphorylation constitute causal agents of many human diseases. Recent studies indicated that phosphorylation of α-synuclein (α-syn) on Serine129 (pS129) is central to the pathogenesis of Parkinson’s Disease (PD). However, the molecular mechanisms of α-syn hyperphosphorylation in Lewy bodies (LBs) are poorly understood, and unraveling the mechanisms that regulate pS129α-syn levels in neuronal cells is key to understanding the pathophysiology of the disease. “in-cell NMR” is a recently developed technique that can be used to characterize the conformation and interactions of proteins inside living cells and at atomic resolution. This project is going to investigate the dephosphorylation and degradation processes of pS129α-syn in neuronal cells by in-cell NMR, and will reveal the role of phosphorylation on the partition of α-syn between the proteasomal and autophagy degragation pathways in neuronal cells. Furthermore, pS129α-syn dephosphorylation and degradation in PD model cells will also be studied. Through this project, we will explore the stability and degradation mechanism of pS129α-syn in neuronal cells, and make knowledge of the molecular mechanism of α-syn hyperphosphorylation and neuronal cell dysfunction in the brain of PD patients, which are of important significance for the study of the pathophysiology of PD.