血浆CNS来源外泌体中寡聚磷酸化α-synuclein对PD病程的提示研究

脑内α-synuclein（α-syn）聚集及磷酸化与帕金森病（PD）病理进程密切相关。血浆中枢神经系统（CNS）来源外泌体中寡聚磷酸化α-syn（p-α-syn）能否成为反映PD致病进程生物标志物有待动物模型及临床样本的验证。本课题拟首先对人血浆CNS来源外泌体中寡聚p-α-syn表达特性及其与PD发病关联性进行考察；通过构建模拟PD病变进程的α-syn预成型原纤维小鼠模型，多时段监测血浆CNS来源外泌体中寡聚p-α-syn的量变与PD定量病理进程的同步联系；在此基础上，建立复杂基质中不同聚集状态p-α-syn非变性电泳分离-高分辨质谱定量方法，对较大样本量不同病程PD病人及健康对照进行靶向检测，并与临床评分作关联性统计学分析，总结验证血浆CNS来源外泌体中寡聚p-α-syn含量比值变化对PD临床病程的有效提示作用。项目的完成将为无创PD病程监测标志物的研究提供有力支撑。

A-synuclein (α-syn) aggregation and phosphorylation in brain is closely related to the pathogenesis of Parkinson's disease (PD). Whether the oligomeric phosphorylated α-syn in plasma central nervous system (CNS) derived exosomes can be a biomarker reflecting the pathogenesis of PD remains to be verified in animal models and clinical samples. This study will firstly investigate the expression characteristics of oligomeric phosphorylated α-syn in CNS derived exosomes in human plasma and its correlation with PD onset. Secondly, an α-syn preformed fibrils mouse model will be constructed to simulate the progression of PD brain lesions, and the correlation between the levels of oligomeric phosphorylated.α-syn in CNS derived exosomes and the quantified progression lesions in the brain will be monitored in different period . On these bases, through the native gel electrophoresis processing before separation, the different states of aggregated phosphorylated α-syn by high-resolution mass spectrometry quantitative method in complex matrix will be established. Larger sample size from different duration of PD patients and healthy controls will be quantitatively detected, and the correlation statistics analysis will be done according to the onset of clinical PD score. Finally, the validation of the rate of oligomeric phosphorylated α-syn in CNS derived exosomes in human plasma and its correlation with the process of PD pathogenesis will be summarized. The completion of the project will provide strong support for the study of non-invasive biomarkers for PD pathogenesis monitoring.