异常聚集的α-突触核蛋白（α-syn）的“朊蛋白样”传播在帕金森病（PD）中的核心作用渐被认可，但确切的机制仍未充分阐明。外泌体是细胞分泌的超微膜性囊泡，可将细胞内的蛋白质长距离递送到“接受细胞”，也能自由穿透血脑屏障，因而在PD的诊治研究中备受瞩目。本课题组前期发现患者血清外泌体中α-syn寡聚体明显增多，随后创新性地将这些外泌体经尾静脉及纹状体注射给小鼠，诱发其PD样行为和病理改变，提示外泌体介导了致病性α-syn从PD患者向小鼠的“传播”。据此，我们拟采用超速离心法、免疫吸附等技术提取PD患者血清中含α-syn寡聚体的外泌体，在细胞及动物模型中观察其对“接受细胞”的选择性传播及其“种子效应”，同时探索抑制外泌体生成以及采用α-syn寡聚体特异性抗体选择性阻断其传输，建立新的干预措施以延缓PD的病理进程，为PD的发病机制探索和防治新策略研发提供科学依据。

Recently, the role of “prion like” propagation of pathogenic α-synuclein (α-syn) in the pathogenesis of Parkinson’s disease (PD) is widely accepted, but the exact underlying mechanisms remain to be elucidated. The idea that exosomes may be involved in the spreading of α-syn is attracting considerable attention. Exosomes are microvesicles secreted by the cells which contains specified proteins, then loaded proteins can be transmitted to distant area and even pass through the blood brain barrier, which may alter the function of the recipient cells in central nervous system. In the previous study, our group demonstrated that α-syn oligomers is obviously abundant in PD patients’ serum derived exosomes compared with controls. Innovatively, we intravenously and striatally injected those exosomes into the mouse, surprisingly induced PD-like behaviors as well as pathological alteration. All these strongly indicate that exosomes are able to mediate pathogenic ingredients (α-syn oligomers) transmission from PD patients to mouse. On this basis, we contrive to reveal the underlying mechanisms as follows: exosomes containing α-syn oligomers will be extracted and purified by high speed centrifugation and immune-capture. Afterwards, exosomes will be added to cells and animals to explore the mechanisms related to their selective delivery and the “seeding” effects in recipient cells. Meanwhile, intervention study will be conducted by inhibition of exosomes biogenesis and interruption of extracellular exosomes transportation utilizing α-syn oligomers specified monoclonal antibody. The fulfillment of the proposed project will provide a novel insight into the pathogenesis of PD and bring inspiration to develop new strategies to halt PD progression.