Department of Environmental and Occupational Health, School of Public Health, Guangdong Medical University, Dongguan 523808, P. R. China.
Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, P. R. China.
J Agric Food Chem. 2021 Nov 24;69(46):13942-13952. doi: 10.1021/acs.jafc.1c04190. Epub 2021 Nov 15.
Rotenone, a component of pesticides, is widely used in agriculture and potentially causes Parkinson's disease (PD). However, the regulatory mechanisms of rotenone-induced PD are unclear. Here, we revealed a novel feedback mechanism of p38-Parkin-ROS regulating rotenone-induced PD. Rotenone treatment led to not only the activation of p38 but also Parkin inactivation and reactive oxygen species (ROS) overproduction in SN4741 cells. Meanwhile, p38 activation regulated Parkin phosphorylation at serine 131 to disrupt Parkin-mediated mitophagy. Notably, both p38 inhibition and Parkin overexpression decreased ROS levels. Additionally, the ROS inhibitor -acetyl-l-cysteine (NAC) inhibited p38 and activated Parkin-mediated mitophagy. Both p38 inhibition and the ROS inhibitor NAC exerted a protective effect by restoring cell death and mitochondrial function in rotenone-induced PD models. Based on these results, the p38-Parkin-ROS signaling pathway is involved in neurodegeneration. This pathway represents a valuable treatment strategy for rotenone-induced PD, and our study provides basic research evidence for the safe use of rotenone in agriculture.
鱼藤酮是一种杀虫剂的成分，广泛应用于农业，并可能导致帕金森病（PD）。然而，鱼藤酮诱导的 PD 的调控机制尚不清楚。在这里，我们揭示了 p38-Parkin-ROS 调节鱼藤酮诱导的 PD 的一种新的反馈机制。鱼藤酮处理不仅导致 p38 的激活，还导致 SN4741 细胞中 Parkin 失活和活性氧（ROS）过度产生。同时，p38 的激活调节 Parkin 丝氨酸 131 的磷酸化，破坏 Parkin 介导的线粒体自噬。值得注意的是，p38 抑制和 Parkin 过表达均降低了 ROS 水平。此外，ROS 抑制剂乙酰半胱氨酸（NAC）抑制 p38 并激活 Parkin 介导的线粒体自噬。p38 抑制和 ROS 抑制剂 NAC 都通过恢复鱼藤酮诱导的 PD 模型中的细胞死亡和线粒体功能发挥保护作用。基于这些结果，p38-Parkin-ROS 信号通路参与神经退行性变。该通路为鱼藤酮诱导的 PD 提供了有价值的治疗策略，本研究为农业中鱼藤酮的安全使用提供了基础研究证据。
