帕金森症致病蛋白α-synuclein在肠脑轴传递的机制研究

The pathological feature of Parkinson's disease (PD) is that α-synuclein (SNCA) aggregates result in dopaminergic neurons death in the substantia nigra pars compacta. However, the mechanism of the formation of SNCA aggregates in the central nervous system has not been clarified. It is found that PD patients often suffer from nonmotor disorders, such as constipation and hyposmia, which can precede the onset of motor symptoms (tremor, rigidity). And SNCA aggregates can be detected in the gastrointestinal tract of PD patients. This suggests that the peripheral nervous system, especially the enteric nervous system, may be involved in the pathogenesis of Parkinson's disease. Because of the lack of good in vitro model of the enteric nervous system, it is not clear whether SNCA aggregates in the gastrointestinal tract can retrograde transmit to the central nervous system and lead to pathological changes. Utilizing the established induction system of the differentiation of human induced pluripotent stem cells (hiPSCs) into enteric neurons, we have discovered that environmental factors, such as rotenone, can.increase the expression and aggregation of SNCA in the enteric neurons. Based on our recent progress, we will examine the pathogenic effect of α-synuclein aggregates on enteric neurons, the transmission route of α-synuclein aggregates to the central nervous system and the mechanism of the transmission using microfluidic neuronal culture device and cell transplantation. Our study would contribute to the exploration of early pathogenesis and prevention for PD, as well as provide deep insight into the important role of the gut-brain axis in the.central nervous system diseases.

帕金森症（PD）的病理特征是聚集的α-突触核蛋白（SNCA）导致中脑黑质致密部的多巴胺能神经元死亡，但SNCA中枢聚集机制尚未阐明。研究发现，PD患者在出现震颤、僵直等运动症状前常有便秘、嗅觉减退等非运动症状，肠神经元可见SNCA聚集，提示外周神经系统，尤其是肠神经系统可能参与了PD的发病过程。因缺少良好的肠神经系统研究模型，胃肠道的SNCA聚集小体是否可以逆行传递到中枢神经系统并导致其病变目前尚不明确。利用课题组前期建立的人iPS细胞高效分化为肠神经元的诱导体系，申请人发现鱼藤酮等环境因子可诱导肠神经元的SNCA表达增加和发生聚集。在此基础上，本研究拟利用微流控神经元培养技术和体内移植等方法，研究SNCA聚集小体对肠神经元的影响、中枢传递的路径和致病作用及其传递的分子机制，这不仅可以为探究PD的发病机制和防治手段提供新的思路，也有助于解析肠脑轴在中枢神经系统疾病中的重要作用。

胃肠功能障碍是帕金森病（Parkinson's Disease, PD）典型的非运动症状之一，直接影响患者的发病和运动症状的复杂化，但目前对帕金森症早期肠道发病机制仍不是很清楚。胃肠功能的正常运行很大程度依赖肠神经系统的调控，神经嵴细胞是包括肠神经系统在内的外周神经系统发生的起源细胞，因此，神经嵴细胞分化来的肠神经元是研究帕金森早期肠道发病机制的理想细胞模型。为此，本项目研究通过建立人多能干细胞定向神经嵴干细胞和肠神经元分化体系，通过环境因子（MPP+、鱼藤酮等）诱导，成功构建了体外帕金森病肠神经系统研究模型，通过检测乳酸脱氢酶（lactate dehydrogenase, LDH）活性及细胞内活性氧（ROS）的形成，初步探讨了环境因子导致帕金森症肠道病变的致病机制。此外，利用慢病毒载体系统和微流控神经元培养技术，初步建立了肠脑轴传递体外研究模型，本项目研究为这类疾病的研究提供了一种新的工具，也为进一步的寻找新治疗靶点和新的治疗方法提供指导。