Microglia toxicology in α-synuclein pathology

Oligomeric α-synuclein (α-syn) could activate microglia and induce inflammation to drive the pathogenesis of Parkinson's disease (PD). Our previous study revealed that significant difference of IL6ST in cerebrospinal fluid of PD patients and a decline in IL6ST/JAK2/STAT3 were also observed in α-syn-induced HMC3 cells. JAK2/STAT3 pathway is not only a novel inflammatory pathway but also involved in ferroptosis progress. In this study, our results demonstrated that α-syn could impair cell activity and promote HMC3 cells differentiation into M2 phenotype. Besides, α-syn stimulation led to the inhibit of IL6ST/JAK2/STAT3 pathway and its downstream target, HIF-1α, in HMC3 cells. We further carried out transcriptomic analysis for α-syn-induced HMC3 cells and GSEA showed an association with ferroptosis. Results above implied the role of STAT3 in α-syn induced ferroptosis. Later, we found out α-syn decreased the phosphorylation of STAT3, which contributed to a remarkable morphological change in mitochondria and transcriptional activation of ferroptosis regulation genes (FRGs), such as ASCL4 and SLC7A11. Moreover, α-syn also promoted ferroptosis in microglia by inhibiting P-STAT3 expression and increasing iron metabolism and lipid peroxidation levels, all of which were reversed by the STAT3 activator. In conclusion, the phosphorylation and activation of STAT3 was an important factor that regulated microglia ferroptosis. α-syn stimulation influenced the cell activity, polarization and cellular toxicology in microglia via modulating IL6ST/ JAK2/STAT3/HIF-1α axis.