Cai Waijiao, Wakamatsu Kazumasa, Zucca Fabio A, Wang Qing, Yang Kai, Mohamadzadehonarvar Niyaz, Srivastava Pranay, Tanaka Hitomi, Holly Gabriel, Casella Luigi, Ito Shosuke, Zecca Luigi, Chen Xiqun
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA; Institutes of Integrative Medicine, Fudan University, Shanghai, China; Department of Integrative Medicine, Huashan Hospital, Shanghai, China.
Institute for Melanin Chemistry, Fujita Health University, Toyoake, Japan.
Prog Neurobiol. 2023 Apr;223:102414. doi: 10.1016/j.pneurobio.2023.102414. Epub 2023 Feb 4.
Neuromelanin (NM) in dopaminergic neurons of human substantia nigra (SN) has a melanic component that consists of pheomelanin and eumelanin moieties and has been proposed as a key factor contributing to dopaminergic neuron vulnerability in Parkinson's disease (PD). While eumelanin is considered as an antioxidant, pheomelanin and related oxidative stress are associated with compromised drug and metal ion binding and melanoma risk. Using postmortem SN from patients with PD or Alzheimer's disease (AD) and unaffected controls, we identified increased L-3,4-dihydroxyphenylalanine (DOPA) pheomelanin and increased ratios of dopamine (DA) pheomelanin markers to DA in PD SN compared to controls. Eumelanins derived from both DOPA and DA were reduced in PD group. In addition, we report an increase in DOPA pheomelanin relative to DA pheomelanin in PD SN. In AD SN, we observed unaltered melanin markers despite reduced DOPA compared to controls. Furthermore, synthetic DOPA pheomelanin induced neuronal cell death in vitro while synthetic DOPA eumelanin showed no significant effect on cell viability. Our findings provide insights into the different roles of pheomelanin and eumelanin in PD pathophysiology. We anticipate our study will lead to further investigations on pheomelanin and eumelanin individually as biomarkers and possibly therapeutic targets for PD.
人类黑质（SN）中多巴胺能神经元的神经黑色素（NM）具有一种黑色素成分，该成分由褐黑素和真黑素部分组成，并且被认为是导致帕金森病（PD）中多巴胺能神经元易损性的关键因素。虽然真黑素被视为一种抗氧化剂，但褐黑素及相关的氧化应激与药物和金属离子结合受损以及黑色素瘤风险有关。利用帕金森病或阿尔茨海默病（AD）患者以及未受影响的对照者的死后黑质，我们发现与对照组相比，帕金森病黑质中L-3,4-二羟基苯丙氨酸（DOPA）褐黑素增加，多巴胺（DA）褐黑素标志物与DA的比率升高。帕金森病组中源自DOPA和DA的真黑素均减少。此外，我们报告帕金森病黑质中DOPA褐黑素相对于DA褐黑素增加。在阿尔茨海默病黑质中，尽管与对照组相比DOPA减少，但我们观察到黑色素标志物未改变。此外，合成的DOPA褐黑素在体外诱导神经元细胞死亡，而合成的DOPA真黑素对细胞活力没有显著影响。我们的研究结果为褐黑素和真黑素在帕金森病病理生理学中的不同作用提供了见解。我们预计我们的研究将导致对褐黑素和真黑素分别作为帕金森病生物标志物以及可能的治疗靶点进行进一步研究。
