mTOR-Mediated Protection Against Atrazine-Induced Ferroptosis and Dopaminergic Neurodegeneration in Parkinson's Disease Models.

Abstract

Atrazine (ATR) is a widely used herbicide known to induce degeneration of nigrostriatal dopaminergic (DA) neurons, leading to a Parkinson's disease (PD)-like syndrome. Ferroptosis, an iron-dependent non-apoptotic cell death, is implicated in various neurodegenerative diseases, though its specific role in PD remains unclear. In this study, 3657 differentially expressed genes associated with PD from the gene expression database were identified, which are enriched in the ferroptosis pathway. Additionally, ATR-induced SD rats and human SH-SY5Y neuroblastoma cells were used to model PD and explore the effects of mTOR on ferroptosis. The results demonstrated that ATR induces ferroptosis, which can be inhibited by pretreatment with Ferrostatin-1. Furthermore, overexpression of mTOR suppressed ATR-induced damage by activating the GPX4 pathway. These findings suggest that mTOR protects against ATR-induced ferroptosis in PD by modulating the GPX4 pathway, highlighting the potential therapeutic value of targeting mTOR and ferroptosis pathways to mitigate ATR-induced neurotoxicity and PD progression.