JWA对百草枯所致多巴胺能神经元氧化损伤的保护作用及机制研究

Paraquat (PQ) is a common environmental toxicant. It has been demonstrated that long-term, low-dose exposure to PQ can cause oxidative damage to dopaminergic neurons, which will ultimately increase the risk of parkinson’s disease (PD). However, the underlying mechanisms still remain unknown. Our preliminary results indicated that JWA, a novel environmental response gene, could help the dopaminergic neurons to escape from PQ induced neurotoxicity. Nuclear factor erythroid 2 - related factor 2 (Nrf2) has been regarded as the core defender to oxidative damage. In this proposal, we will apply neuronal JWA specific knockout and inducible overexpressed mice as well as the cell models to uncover how JWA activates Nrf2 to protect PQ induced neurotoxicity. In addition, we also attempt to investigate the preventive role of JWA derived peptide (PJP1) in PQ triggered damage. Our results will bring new insights and strategies against the neurotoxicity of PQ.

农药百草枯（Paraquat, PQ）是常见的环境毒物。长期、低剂量、慢性PQ暴露造成中脑多巴胺能神经元氧化损伤，增加了帕金森病的发病风险，目前尚无有效手段预防PQ引起的神经毒性。申请人研究生阶段一直从事环境应答基因JWA结构和功能关系的研究，初步研究发现JWA基因能够拮抗PQ引起的神经毒性。本课题拟利用已成功构建的模式生物（神经系统JWA基因特异性剔除和高表达小鼠）及相应的细胞模型，系统解析JWA通过调控Nrf2抵抗PQ所致多巴胺能神经元氧化损伤的毒作用机制，同时积极探索JWA活性多肽的保护作用，为今后精准预防环境毒物PQ引起的神经毒性提供新的科学依据。

长期、低剂量、慢性农药百草枯（Paraquat, PQ）暴露可造成中脑多巴胺能神经元损伤，增加帕金森病的发病风险，但其毒作用机制尚未完全阐明，且缺乏有效的干预策略。本课题按照项目计划任务书开展研究，以环境应答基因JWA为抓手，结合相应的小鼠和细胞模型，证实了JWA能够通过调控p62-Keap1-Nrf2信号轴拮抗PQ所致的多巴胺能神经元氧化损伤及其作用机制，并且发现JWA活性多肽可以模拟JWA功能，发挥保护作用。本项目已经完成了既定的研究计划，取得的研究结果包括以下几方面：（1）阐明JWA是拮抗PQ所致神经毒性的关键分子；（2）证实了JWA通过激活p-AKT，促使p62蛋白S351位点发生磷酸化修饰；p-p62（S351）竞争性结合Keap1蛋白Kelch结构域，使得p62发生泛素化降解，释放被Keap1扣押在胞浆内的Nrf2蛋白；活化的Nrf2从胞浆内易位到细胞核中，增加下游抗氧化应激基因表达，最终拮抗PQ引起的神经毒性；（3）JWA活性多肽能够模拟JWA抗氧化应激的功能，抵抗PQ引起的神经毒性。本项目为今后有效防治PQ所致的神经毒性提供科学依据。