Melatonin MT1 receptors regulate the Sirt1/Nrf2/Ho-1/Gpx4 pathway to prevent α-synuclein-induced ferroptosis in Parkinson's disease

IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Journal of Pineal Research Pub Date : 2024-03-15 DOI:10.1111/jpi.12948
Qian-Kun Lv, Kang-Xin Tao, Xiao-Yu Yao, Meng-Zhu Pang, Bing-Er Cao, Chun-Feng Liu, Fen Wang
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Abstract

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.

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褪黑素MT1受体调节Sirt1/Nrf2/Ho-1/Gpx4通路,以防止帕金森病中α-突触核蛋白诱导的铁突变。
帕金森病(PD)是一种神经退行性疾病,以多巴胺能(DA)神经元的丧失和α-突触核蛋白(α-syn)的聚集为特征。铁变态反应是一种由铁积累和脂质过氧化诱导的细胞死亡形式,与帕金森病的发病机制有关。目前尚不清楚褪黑激素受体1(MT1)是否会调节α-syn和铁突变在帕金森病中的作用。在这里,我们利用α-syn预成纤维(PFFs)诱导体内和体外的帕金森病模型。在帕金森病小鼠中,α-syn的聚集导致铁沉积和铁变态反应增加。MT1基因敲除会加剧这些变化,导致更多的DA神经元缺失和严重的运动障碍。MT1基因敲除还抑制了Sirt1/Nrf2/Ho1/Gpx4通路,降低了对铁沉积的抵抗力,并抑制了铁蛋白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。敲除MT1会增强α-syn PFF诱导的细胞内α-syn聚集,抑制Sirt1/Nrf2/Ho1/Gpx4通路和Fth1蛋白的表达,从而加剧铁蛋白沉积。相反,过量表达 MT1 则会逆转这些影响。我们的研究结果揭示了一种新的机制,即MT1活化可防止α-syn诱导的帕金森病铁变态反应,突出了MT1在帕金森病中的神经保护作用。
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来源期刊
Journal of Pineal Research
Journal of Pineal Research 医学-内分泌学与代谢
CiteScore
17.70
自引率
4.90%
发文量
66
审稿时长
1 months
期刊介绍: The Journal of Pineal Research welcomes original scientific research on the pineal gland and melatonin in vertebrates, as well as the biological functions of melatonin in non-vertebrates, plants, and microorganisms. Criteria for publication include scientific importance, novelty, timeliness, and clarity of presentation. The journal considers experimental data that challenge current thinking and welcomes case reports contributing to understanding the pineal gland and melatonin research. Its aim is to serve researchers in all disciplines related to the pineal gland and melatonin.
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