Extracellular α-Synuclein Modulates Iron Metabolism Related Proteins via Endoplasmic Reticulum Stress in MES23.5 Dopaminergic Cells

Alpha-synuclein plays a vital role in the pathology of Parkinson's disease (PD). Spreading of alpha-synuclein in neighboring cells was believed to contribute to progression in PD. How alpha-synuclein transmission affects adjacent cells is not full elucidated. Here, we used recombinant alpha-synuclein to mimic intercellular transmitted alpha-synuclein in MES23.5 dopaminergic cells, to investigate whether and how it could modulate iron metabolism. The results showed that alpha-synuclein treatment up-regulated divalent metal transporter 1 (DMT1) and down-regulated iron transporter (FPN), also up-regulated iron regulatory protein 1 (IRP1) protein levels and hepcidin mRNA levels. Endocytosis inhibitor dynasore pretreatment completely abolished and even reversed the upregulation of DMT1 and IRP1 induced by alpha-synuclein, however, FPN down-regulation was partially blocked by dynasore. Autophagy-inducing agent rapamycin reversed DMT1 up-regulation and FPN down-regulation, and fully blocked the upregulation of IRP1. Elevated hepcidin levels induced by alpha-synuclein was fully blocked by dynasore pretreatment, however, even higher with rapamycin pretreatment. Alpha-synuclein treatment triggered endoplasmic reticulum (ER) stress. ER stress inducer thapsigargin induced similar responses elicited by alpha-synuclein. ER stress inhibitor salubrinal blocked the up-regulation of IRP1 and hepcidin, as well as DMT1 up-regulation and FPN down-regulation, also dramatically abolished cAMP-response elements binding protein phosphorylation induced by alpha-synuclein. Taken together, these finding indicated that extracellular alpha-synuclein could regulate cellular iron metabolism, probably mediated by ER stress. It provides novel evidence to elucidate the relationships between transmitted alpha-synuclein and iron metabolism disturbance in PD.