人黑质(SN)多巴胺能神经元中的神经黑色素(NM)具有黑色素成分,该成分由软黑素和真黑素部分组成,已被认为是导致帕金森病(PD)多巴胺能神经元易损性的关键因素。虽然Eumelanin被认为是一种抗氧化剂,pheomelanin和相关的氧化应激与受损的药物和金属离子结合和黑色素瘤风险相关。使用来自PD或阿尔茨海默病(AD)患者和未受影响的对照组的验尸SN,我们发现,与对照组相比,PDSN中L-3,4-二羟基苯丙氨酸(DOPA)pheomelanin增加,多巴胺(DA)pheomelanin标记物与DA的比值增加.来自DOPA和DA的Eumelanins在PD组中降低。此外,我们报告了PDSN中DOPApheomelanin相对于DApheomelanin的增加。在ADSN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自美拉素在体外诱导神经元细胞死亡,而合成的DOPA自美拉素对细胞活力没有显着影响。我们的发现提供了对pheomelanin和eumelanin在PD病理生理学中的不同作用的见解。我们预计我们的研究将导致进一步研究菲莫拉宁和真美拉宁分别作为PD的生物标志物和可能的治疗靶标。
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.