DOPA pheomelanin is increased in nigral neuromelanin of Parkinson's disease. (April 2023)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Progress in neurobiology. Volume 223(2023)
• Publication Date: 2023-04
• Subjects: Parkinson's disease -- Pheomelanin -- Eumelanin -- DOPA -- Dopamine -- Neuromelanin; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2023.102414
• Languages: English
• ISSNs: 0301-0082

Abstract

Abstract: 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. Highlights: Total neuromelanin derived from both DOPA and DA is decreased in PD postmortem SN. DOPA pheomelanin is increased and eumelanin derived from both DOPA and DA is reduced in PD postmortem SN. Synthetic DOPA pheomelanin promotes neuronal cell death while DOPA eumelanin does not influence neuronal cell viability.