α-突触核蛋白（α-Syn）的过表达及其毒性聚集是帕金森疾病（PD）发生的重要诱因之一。用于早期PD治疗的多巴胺受体激动剂因降效及耐受而在临床备受关注，但其发生机制尚不明确。已有文献报道，α-Syn可调控uptake 1转运体功能并在神经退行性疾病进程中占有重要地位。鉴于uptake 2（OCT2/3、PMAT）与uptake 1转运体脑内分布与功能高度相似，本项目以普拉克索和罗匹尼罗为研究对象，分别采用共转染细胞、小鼠突触小体、人源LUHMES细胞模型研究α-Syn对uptake 2转运体介导药物细胞摄取的影响；整体动物模型阐释α-Syn调控 uptake 2转运体功能从而导致药物降效的分子药动学机制；从细胞与整体动物水平探讨α-Syn影响uptake 2转运体功能的分子生物学机理。研究结果将揭示多巴胺受体激动剂抗PD降效机制，为解决临床抗PD治疗耐受问题提供新的思路与策略。

The overexpression of α-synuclein (α-Syn) and its aggregation is one of the most important causes for Parkinson’s disease (PD). In clinic, concerns have been increasingly attracted due to reduced therapeutic effect and tolerance to dopamine (DA) agonists in the treatment of early stage of PD. However, the underlying mechanism remains unknown. Regulation of uptake 1 transporters mediated by α-Syn plays a critical role in the process of neurodegenerative diseases. The high similarity of brain distribution and function between uptake 1 and uptake 2 transporters (OCT2/3 and PMAT) has been reported. In this study, pramipexole and ropinirole will be chosen as model drugs. Initially, effect of α-Syn on uptake 2 transporters mediated cellular uptake of pramipexole and ropinirole will be investigated using co-transfected cells, mouse synaptosomes and LUHMES cells. Furthermore, α-Syn null and normal PD mouse models will be constructed to elucidate the molecular pharmacokinetic mechanism for decreased therapeutic effect of pramipexole and ropinirole mediated by regulation of uptake 2 transporter function. Finally, the molecular biological mechanism of α-Syn mediated OCT2/3 and PMAT activity alteration will be explored at both cell and whole animal levels. The research results will elucidate the mechanism for declined therapeutic efficacy of DA agonists, which provides novel ideas and strategies to solve the drug tolerance during clinical PD treatment.