帕金森氏病（PD）是一种多巴胺能神经元退化性疾病,研究显示a-synuclein对多巴胺神经元有明显毒性作用,其机制不清。我们前期工作显示a-synuclein在PD细胞模型中明显减低，其oligomer与TLR4含量明显增加,共聚焦预试验指出a-synuclein与TLR2受体似有共定位。我们将在PD模型中明确胞外分泌的a-synuclein oligomer对多巴胺神经元损害及其与TLR2/4的共表达, 并观察a-synuclein oligomer对TLR2/4的激活,证实其下游炎性通路MyD88-Juk-AP1/p38MAPK-NFkB激活对多巴胺神经元的损害,同时探讨胞外分泌a-synuclein oligomer与TLR2/4在小胶质细胞激活产生的炎性反应中与多巴胺神经元损伤间的相关性，以阐释胞外分泌a-synuclein oligomer-TLR2/4在PD发展中的病理机制。

Parkinson's Disease (PD) is the second most common neurodegenerative disorder following Alzheimer's Disease (AD),and is characterized by a disturbance of the central dopaminergic system. Several lines of studies have shown that a-synuclein displays neurotoxicity to dopaminergic neurons; however, the precise machenisms are unknown. Our preliminary study shows that a-synuclein pronouncedly decreases in 6-OHDA-lesioned PC 12 cells, the in vitro PD model, but its oligomer and toll like receptor 4 are profoundly upregulated. Our preliminary study also shows that a-synuclein seems to co-locolize with toll like receptor 2. Thus We aim to investigate in 6-OHDA-induced PC12 how exocytotic oligomer a-synuclein displays deleterious effects in dopaminergic neurons, and its correlations with toll like receptor 2/4 and how the oligomer activates toll like receptor 2/4. We would like to verify that the possible downstream inflammatory signaling pathway MyD88-Juk-AP1/p38MAPK-NFkB may cause damage in PC12. In addition, we would like to explore how the exocytotic oligomer a-synuclein activates microglia and what the association of inflammatory responses with toll like receptor 2/4 and PC12 is. Through this study, we aim to explore the pathological mechanisms how exocytotic oligomer a-synuclein-toll like receptor 2/4 influences the progression of PD.