α‑Synuclein Regulates Iron Homeostasis via Preventing Parkin-Mediated DMT1 Ubiquitylation in Parkinson’s Disease Models

Iron metabolism imbalance plays a key role in the neurodegeneration of Parkinson’s disease (PD), thus iron homeostasis should be tightly controlled by iron transporters. α-Synuclein (α-Syn) serves as a ferrireductase and iron-binding protein, which is supposed to be linked with iron metabolism, but little is known about how α-Syn affects iron homeostasis in PD. Our previous findings that up-regulation of divalent metal transporter 1 (DMT1) accounted for the nigral iron accumulation in PD raised the question whether α-Syn disturbed iron homeostasis by modulating DMT1 expression. Using α-Syn overexpressed SH-SY5Y cells and mutant human A53T α-Syn transgenic mice, we found that α-Syn could up-regulate DMT1 protein levels, followed by enhanced ferrous iron influx and subsequent aggravated oxidative stress injury. Mechanistic studies identified that α-Syn-induced p38 mitogen-activated protein kinase (MAPK) activation phosphorylated parkin at Ser131, which inactivated parkin’s E3 ubiquitin ligase activity and further reduced DMT1 ubiquitylation level. Our findings revealed that α-Syn affected brain iron homeostasis through modulating DMT1 protein stability and altering cellular iron uptake, which might provide direct evidence for the involvement of α-Syn in iron metabolism dysfunction and provide insight into PD-associated nigral iron deposition.