Ferroptosis Induced by Pb Exposure Causes Parkinson’s Disease-Related Dopaminergic Neuronal Death

Lead (Pb) exposure is strongly associated with neurodegenerative diseases such as Parkinson's disease (PD). A prominent pathological feature of PD is the degeneration of dopaminergic (DA) neurons. However, the molecular mechanisms underlying Pb-induced DA neuron loss have been insufficiently explored. This study investigated these mechanisms using both <i>in vitro</i> DA neuron cell models and <i>in vivo</i> fly models, demonstrating that ferroptosis is the primary driver of Pb-induced DA neuron death. Mechanistically, Pb²⁺ directly bound to Glu-486/Glu-316 residues of System Xc^-, inhibiting SLC7A11-mediated cystine uptake and depleting glutathione (GSH), thereby triggering ferroptosis. Notably, differentiated DA neurons exhibited heightened sensitivity to Pb-induced ferroptosis, as their cystine uptake was more readily inhibited by Pb exposure than that in mature neurons. These <i>in vitro</i> findings were corroborated in fly models, where Pb exposure during the larval stage resulted in more pronounced PD phenotypes compared with exposure during the adult stage. Notably, administration of GSH precursor alleviated these PD phenotypes in DA neuron numbers and behavior with more effective rescue observed in the larval stage. Consequently, our findings provide crucial data for developing future strategies to mitigate environmental Pb exposure and prevent PD.