Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons and aggregation of α‐synuclein (α‐syn). Ferroptosis, a form of cell death induced by iron accumulation and lipid peroxidation, is involved in the pathogenesis of PD. It is unknown whether melatonin receptor 1 (MT1) modulates α‐syn and ferroptosis in PD. Here, we used α‐syn preformed fibrils (PFFs) to induce PD models in vivo and in vitro. In PD mice, α‐syn aggregation led to increased iron deposition and ferroptosis. MT1 knockout exacerbated these changes and resulted in more DA neuronal loss and severe motor impairment. MT1 knockout also suppressed the Sirt1/Nrf2/Ho1/Gpx4 pathway, reducing resistance to ferroptosis, and inhibited expression of ferritin Fth1, leading to more release of ferrous ions. In vitro experiments confirmed these findings. Knockdown of MT1 enhanced α‐syn PFF‐induced intracellular α‐syn aggregation and suppressed expression of the Sirt1/Nrf2/Ho1/Gpx4 pathway and Fth1 protein, thereby aggravating ferroptosis. Conversely, overexpression of MT1 reversed these effects. Our findings reveal a novel mechanism by which MT1 activation prevents α‐syn‐induced ferroptosis in PD, highlighting the neuroprotective role of MT1 in PD.

中文翻译：

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褪黑素 MT1 受体调节 Sirt1/Nrf2/Ho-1/Gpx4 通路预防帕金森病中 α-突触核蛋白诱导的铁死亡

帕金森病 (PD) 是一种神经退行性疾病，其特征是多巴胺能 (DA) 神经元丧失和 α-突触核蛋白 (α-syn) 聚集。铁死亡是一种由铁积累和脂质过氧化诱导的细胞死亡形式，参与 PD 的发病机制。目前尚不清楚褪黑激素受体 1 (MT1) 是否调节 PD 中的 α-syn 和铁死亡。在这里，我们使用 α-syn 预制原纤维 (PFF) 在体内和体外诱导 PD 模型。在 PD 小鼠中，α-syn 聚集导致铁沉积增加和铁死亡。 MT1 敲除加剧了这些变化，导致更多 DA 神经元损失和严重的运动障碍。 MT1敲除还抑制Sirt1/Nrf2/Ho1/Gpx4通路，降低对铁死亡的抵抗力，并抑制铁蛋白Fth1的表达，导致更多的亚铁离子释放。体外实验证实了这些发现。 MT1的敲低增强了α-syn PFF诱导的细胞内α-syn聚集，并抑制了Sirt1/Nrf2/Ho1/Gpx4通路和Fth1蛋白的表达，从而加剧了铁死亡。相反，MT1 的过度表达可以逆转这些效应。我们的研究结果揭示了 MT1 激活可防止 PD 中 α-syn 诱导的铁死亡的新机制，强调了 MT1 在 PD 中的神经保护作用。