Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, PR China; Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, PR China.
Department of Emergency Intensive Care Unit, Affiliated Dongguan People's Hospital, Southern Medical University, Dongguan, Guangdong, PR China.
Ecotoxicol Environ Saf. 2023 Mar 1;252:114630. doi: 10.1016/j.ecoenv.2023.114630. Epub 2023 Feb 8.
Rotenone, a widely used pesticide, causes dopaminergic neurons loss and increase the risk of Parkinson's disease (PD). However, few studies link the role of PARP1 to neuroinflammatory response and autophagy dysfunction in rotenone-induced neurodegeneration. Here, we identified that PARP1 overactivation caused by rotenone led to autophagy dysfunction and NLRP3-mediated inflammation. Further results showed that PARP1 inhibition could reduce NLRP3-mediated inflammation, which was effectively eliminated by TFEB knockdown. Moreover, PARP1 poly(ADP-ribosyl)ated TFEB that reduced autophagy. Of note, PARP1 inhibition could rescue rotenone-induced dopaminergic neurons loss. Overall, our study revealed that PARP1 blocks autophagy through poly (ADP-ribosyl)ating TFEB and inhibited NLRP3 degradation, which suggests that intervention of PARP1-TFEB-NLRP3 signaling can be a new treatment strategy for rotenone-induced neurodegeneration.
鱼藤酮是一种广泛使用的杀虫剂，会导致多巴胺能神经元丧失，并增加帕金森病（PD）的风险。然而，很少有研究将 PARP1 的作用与鱼藤酮诱导的神经退行性变中的神经炎症反应和自噬功能障碍联系起来。在这里，我们发现鱼藤酮引起的 PARP1 过度激活导致自噬功能障碍和 NLRP3 介导的炎症。进一步的结果表明，PARP1 抑制可以减少 NLRP3 介导的炎症，而 TFEB 敲低可以有效消除这种炎症。此外，PARP1 多聚（ADP-核糖）化 TFEB 减少了自噬。值得注意的是，PARP1 抑制可以挽救鱼藤酮诱导的多巴胺能神经元丧失。总的来说，我们的研究表明，PARP1 通过多聚（ADP-核糖）化 TFEB 来阻断自噬，并抑制 NLRP3 的降解，这表明 PARP1-TFEB-NLRP3 信号通路的干预可能是鱼藤酮诱导的神经退行性变的一种新的治疗策略。
