Institute of Toxicology, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, People's Republic of China.
Neurotox Res. 2021 Aug;39(4):1076-1086. doi: 10.1007/s12640-021-00344-y. Epub 2021 Mar 1.
Autophagy is believed to be essential for the maintenance of axonal homeostasis in neurons. However, whether autophagy is causally related to the axon degeneration in organophosphorus-induced delayed neuropathy (OPIDN) still remains unclear. This research was designed to investigate the role of autophagy in axon degeneration following tri-ortho-cresyl phosphate (TOCP) in an in vitro model. Differentiated wild-type and Atg7 neuro-2a (N2a) cells were treated with TOCP for 24 h. Axonal degeneration in N2a cells was quantitatively analyzed; the key molecules responsible for axon degeneration and its upstream signaling pathway were determined by Western blotting and real-time PCR. The results found that Atg7 cells exhibited a higher resistance to TOCP insult than wild-type cells. Further study revealed that TOCP caused a significant decrease in pro-survival factors NMNATs and SCG10 and a significant increase in pro-degenerative factor SARM1 in both cells. Notably, Atg7 cells presented a higher level of pro-survival factors and a lower level of pro-degenerative factors than wild-type cells in the same setting of TOCP administration. Moreover, DLK-MAPK pathway was activated following TOCP. Altogether, our results suggest that autophagy is able to affect TOCP-induced axonal injury via regulating the balance between pro-survival and pro-degenerative factors, providing a promising avenue for the potential therapy for OPIDN patients.
自噬被认为对神经元轴突的稳态维持至关重要。然而，自噬是否与有机磷诱导的迟发性神经病（OPIDN）中的轴突退化有因果关系尚不清楚。本研究旨在探讨自噬在三邻甲苯磷酸酯（TOCP）诱导的体外模型中对轴突退化的作用。用 TOCP 处理分化的野生型和 Atg7 神经-2a（N2a）细胞 24 小时。定量分析 N2a 细胞中的轴突退化；通过 Western blot 和实时 PCR 确定负责轴突退化及其上游信号通路的关键分子。结果发现，Atg7 细胞比野生型细胞对 TOCP 损伤具有更高的抗性。进一步的研究表明，TOCP 导致两种细胞中的存活因子 NMNATs 和 SCG10 显著减少，退化因子 SARM1 显著增加。值得注意的是，在相同的 TOCP 给药条件下，Atg7 细胞中的存活因子水平较高，退化因子水平较低。此外，DLK-MAPK 通路在 TOCP 后被激活。总之，我们的结果表明，自噬能够通过调节存活因子和退化因子之间的平衡来影响 TOCP 诱导的轴突损伤，为 OPIDN 患者的潜在治疗提供了有希望的途径。
