Despite 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.

尽管对帕金森病（PD）进行了数十年的深入研究，但这种常见的神经退行性疾病仍然无法治愈。我们假设异常铁积累是 PD 标志出现的共同线索，即线粒体功能障碍和 α-突触核蛋白积累。我们研究了大脑中主要铁调节剂铁调素的强大作用。在鱼藤酮和 6-羟基多巴胺 PD 模型中，通过基于病毒的策略过度表达铁调素可防止多巴胺神经元损失，并抑制帕金森症的主要病理以及运动缺陷。铁调素通过减少细胞和线粒体铁积累来保护鱼藤酮诱导的线粒体缺陷。此外，铁调素可减少 α-突触核蛋白的积累，并通过降低铁含量促进 α-突触核蛋白的清除，从而激活自噬。我们的研究结果不仅指出了铁超负荷在 PD 发病机制中的关键作用，而且还证明通过铁调素靶向脑铁水平是一个有前途的治疗方向。