摘要：SummaryDespite intensive research on Parkinson disease (PD) for decades, this common neurodegenerative disease remains incurable. We hypothesize that abnormal iron accumulation is a common thread underlying the emergence of the hallmarks of PD, namely mitochondrial dysfunction and α-synuclein accumulation. We investigated the powerful action of the main iron regulator hepcidin in the brain. In both the rotenone and 6-hydroxydopamine models of PD, overexpression of hepcidin by means of a virus-based strategy prevented dopamine neuronal loss and suppressed major pathologies of Parkinsonism as well as motor deficits. Hepcidin protected rotenone-induced mitochondrial deficits by reducing cellular and mitochondrial iron accumulation. In addition, hepcidin decreased α-synuclein accumulation and promoted clearance of α-synuclein through decreasing iron content that leads to activation of autophagy. Our results not only pinpoint a critical role of iron-overload in the pathogenesis of PD but also demonstrate that targeting brain iron levels through hepcidin is a promising therapeutic direction.Graphical AbstractDisplay OmittedHighlights•Hepcidin rescues motor deficits and dopaminergic neurodegeneration in PD models•Hepcidin represses iron accumulation and mitochondrial deficits in Parkinsonism•Hepcidin promotes clearance of α-synuclein via autophagy activation in PD model•Manipulating brain hepcidin level has potential application in treating PDMolecular Biology; Neuroscience ; Cell Biology
