Ferroptosis was more initial in cell death caused by iron overload and its underlying mechanism in Parkinson's disease.

Abstract Ferroptosis, an iron-dependent nonapoptotic cell death, was referred in neurodegenerative diseases, but its role in Parkinson's disease remains unclear. Here, we used ferric ammonium citrate (FAC) to treat dopaminergic cell to mimic the iron overload during the progression of Parkinson's disease (PD). We found that the cell death types of iron-overloaded dopaminergic cells induced by concentrations of FAC were different. Ferroptosis firstly occurred in a relatively low concentration of FAC-treated group, and then apoptosis appeared in response to the increased iron doses. Moreover, both ferroptosis and apoptosis caused by iron overload could be rescued by inhibitors of ferroptosis, but inhibitors of apoptosis did not prevent the occurrence of ferroptosis. We verified that ferroptosis occurred before apoptosis in α-SynA53T homozygous PD mice model. The underlying mechanism might be associated with the p53 signaling pathway, but not MAPK signaling pathway. Collectively, our results revealed a previously unappreciated role of ferroptosis in the early stages of PD and indicated that ferroptosis could elicit apoptosis in cell death caused by iron overload.