帕金森病关键蛋白α-syn与红细胞形态和功能异常相关性及其机制研究

The neurodegenerative diseases represented by Parkinson's disease have become a major social issue that needs urgent attention in China. The relationship between misfolding and multimerization of the α-synuclein (α-syn) and Parkinson's disease has been widely studied. Moreover, it has been found that the abundance of α-syn protein in the peripheral circulating blood system is significantly higher than that in the central nervous system, which indicates α-syn is a potential diagnostic marker for Parkinson's disease. The applicant's previous research found that compared with healthy controls, patients with Parkinson's disease had abnormal red blood cell morphology. At the same time, α-syn oligomers on the red blood cell membrane were found to be significantly higher than healthy controls. These results suggest that the oligomeric form of α-syn may be a potential diagnostic marker and is worthy of further study. Combined with results from Parkinson's disease model mice, it is suggested that α-syn oligomers on the red blood cell membrane are associated with abnormal red blood cell morphology. Therefore, the applicant proposes two scientific hypotheses on the mechanism of oligomeric α-syn: ①Anemia caused by oligomeric α-syn may be one of the early signs of the pathological process of Parkinson's disease. ② Anemia and Parkinson's disease may share a common pathogenic factor, oligomeric α-syn. Therefore, the applicant intends to take advantages of existing clinical resources to analyze the α-syn abundance on the cytoplasm and membrane of red blood cells by establishing a clinical cohort with "Parkinson’s disease group-healthy control group" in order to screen for new early diagnosis markers of Parkinson's disease. At the same time, the effect of α-syn oligomers on the morphology and function of red blood cells and its regulation mechanism will be explored using Parkinson's disease related transgenic mice and in vitro cell models. Furthermore, whether α-syn oligomers can directly participate in the regulation of red blood cell life rhythm will be investigated. This study will provide a theoretical basis for erythrocyte morphology and α-syn oligomer content on the cell membrane as biomarkers for early screening and diagnosis of Parkinson's disease.

以帕金森病为代表的神经退行性疾病已成为我国目前亟需关注的重大社会问题。帕金森病关键蛋白α-突触核蛋白的错误折叠并多聚化与帕金森病的关系已被广泛研究，外周循环血中的α-syn蛋白丰度明显高于中枢神经系统。申请人前期研究发现，相对于健康对照，帕金森病患者的红细胞形态异常，同时红细胞膜上α-syn寡聚体显著高于健康对照。结合帕金森病模型小鼠的研究，提示红细胞膜上α-syn寡聚体与红细胞形态异常相关。因此，申请人对α-syn的作用机制提出两个假说：①α-syn寡聚体导致的贫血可能是帕金森病病理进程的早期表现。②贫血和帕金森病拥有共同的致病因子，α-syn寡聚体。本项目拟建立“帕金森组-健康对照组”的临床队列，以期筛选出新的帕金森病早期诊断标志物。同时应用帕金森病转基因小鼠和体外细胞模型研究α-syn对红细胞的形态和功能的影响及其作用机制，探讨红细胞膜上α-syn能否直接参与红细胞生命节律的调节。

以帕金森病为代表的神经退行性疾病已成为我国目前亟需高度关注的重大社会问题。帕金森病关键蛋白α-突触核蛋白（α-syn）的错误折叠并多聚化与帕金森病的关系已经被广泛研究。循环血中的α-syn蛋白丰度显著高于中枢神经系统。本项目研究发现，相对于健康对照，帕金森病患者的红细胞形态异常，同时，红细胞细胞膜上α-syn寡聚体显著高于健康对照。这提示寡聚形式的α-syn蛋白以及红细胞形态可能是潜在的诊断标志物。结合帕金森病模型小鼠的研究结果，本研究提出假设红细胞膜上α-syn寡聚体与红细胞形态异常相关。SNCA敲除小鼠红细胞形态显著优于野生型对照小鼠直接证明寡聚形式的α-突触核蛋白影响红细胞形态。在进一步的红细胞体外实验和小鼠体内实验证明红细胞细胞膜上α-syn寡聚体通过红细胞钙内流影响红细胞形态。本研究发现帕金森病患者的红细胞普遍可见变形，表面出现许多突起，与健康对照的红细胞有显著差异，为帕金森病的临床诊断或辅助诊断提供潜在的检测指标。本研究探索了病理性聚集体形式α-突触核蛋白引起帕金森病患者红细胞形态异常的分子机制，为进一步探索帕金森病的发病机制提供新的实验证据和并为早期帕金森干预药物的研究提供理论基础。