Hepcidin Decreases Rotenone-Induced α-Synuclein Accumulation via Autophagy in SH-SY5Y Cells

Parkinson's disease (PD) is a neurodegenerative disorder, and the hallmarks of this disease include iron deposition and alpha-synuclein (alpha-syn) aggregation. Hepcidin could reduce iron in the central and peripheral nervous systems. Here, we hypothesized that hepcidin could further decrease alpha-syn accumulation via reducing iron. Therefore, rotenone or alpha-syn was introduced into human neuroblastoma SH-SY5Y cells to imitate the pathological progress of PD in vitro. This study investigated the clearance effects of hepcidin on alpha-syn induced by a relatively low concentration of rotenone exposure or alpha-syn overexpression to elucidate the potential clearance pathway involved in this process. We demonstrated that SH-SY5Y cell viability was impaired after rotenone treatment in a dose-dependent manner. alpha-syn expression and iron content increased under a low concentration rotenone (25 nM for 3 days) treatment in SH-SY5Y cells. Pre-treatment with hepcidin peptide suppressed the abovementioned effects of rotenone. However, hepcidin did not affect treatment with rotenone under high iron conditions. Hepcidin also played a role in reducing alpha-syn accumulation in rotenone and alpha-syn overexpression conditions. We identified that the probable clearance effect of hepcidin on alpha-syn was mediated by the autophagy pathway using pretreatment with autophagy inhibitors (3-MA and CQ) and detection of autophagy protein markers (LC3II/I and p62). In conclusion, hepcidin eliminated alpha-syn expression via the autophagy pathway in rotenone-treated and alpha-syn overexpression SH-SY5Y cells. This study highlights that hepcidin may offer a potential therapeutic perspective in alpha-syn accumulation diseases.