Melanocortin 1 receptor activation protects against alpha-synuclein pathologies in models of Parkinson's disease.
Melanocortin 1 receptor activation protects against alpha-synuclein pathologies in models of Parkinson's disease.
复制标题
在帕金森氏病模型中，黑素皮质素1受体的激活对α-突触核蛋白的病理具有保护作用。
DOI：
10.1186/s13024-022-00520-4
复制
发表时间：
2022-02-23
影响因子：
15.1
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Cai W;Srivastava P;Feng D;Lin Y;Vanderburg CR;Xu Y;Mclean P;Frosch MP;Fisher DE;Schwarzschild MA;Chen X
流行病学研究表明黑色素瘤相关色素沉着基因黑皮质素1受体（MC 1 R）与帕金森病（PD）风险之间存在联系。我们以前表明，MC 1 R信号可以促进黑质纹状体多巴胺能神经元的存活。本研究探讨了MC 1 R对α-突触核蛋白（αSyn）诱导的神经毒性的神经保护潜力，α-突触核蛋白是PD遗传学和发病机制的关键参与者。在具有MC 1 R失活突变、过表达其野生型转基因或用MC 1 R激动剂处理的小鼠中评估由aSyn局部过表达诱导的黑质多巴胺能神经元毒性。体外研究了核因子红细胞2相关因子2（Nrf 2）在MC 1 R介导的抗αSyn保护中的作用。此外，MC 1 R的表达，确定在人死后中脑与PD患者和未受影响的受试者。在黑质纹状体通路中靶向表达αSyn可诱导MC 1 R突变小鼠的突触核蛋白病理恶化，伴有神经炎症和改变的Nrf 2反应，并可通过人MC 1 R转基因逆转。两种MC 1 R激动剂对α-Syn诱导的多巴胺能神经毒性具有神经保护作用。体外实验表明，Nrf 2是MC 1 R效应的必要介质。最后，MC 1 R存在于人黑质的多巴胺能神经元中，并且在PD患者的组织水平上似乎减少。我们的研究支持了MC 1 R和αSyn之间的相互作用，这种相互作用可能是由神经元MC 1 R通过Nrf 2介导的。它为MC 1 R作为治疗靶点提供了证据，并为PD的MC 1 R激活策略的开发提供了理论基础。在线版本包含补充材料，可通过10.1186/s13024-022-00520-4获得。
Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R) and risk of Parkinson’s disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neurotoxicity induced by alpha-synuclein (αSyn), a key player in PD genetics and pathogenesis. Nigral dopaminergic neuron toxicity induced by local overexpression of aSyn was assessed in mice that have an inactivating mutation of MC1R, overexpress its wild-type transgene, or were treated with MC1R agonists. The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in MC1R-mediated protection against αSyn was characterized in vitro. Furthermore, MC1R expression was determined in human postmortem midbrain from patients with PD and unaffected subjects. Targeted expression of αSyn in the nigrostriatal pathway induced exacerbated synuclein pathologies in MC1R mutant mice, which were accompanied by neuroinflammation and altered Nrf2 responses, and reversed by the human MC1R transgene. Two MC1R agonists were neuroprotective against αSyn-induced dopaminergic neurotoxicity. In vitro experiments showed that Nrf2 was a necessary mediator of MC1R effects. Lastly, MC1R was present in dopaminergic neurons in the human substantia nigra and appeared to be reduced at the tissue level in PD patients. Our study supports an interaction between MC1R and αSyn that can be mediated by neuronal MC1R possibly through Nrf2. It provides evidence for MC1R as a therapeutic target and a rationale for development of MC1R-activating strategies for PD. The online version contains supplementary material available at 10.1186/s13024-022-00520-4.