DOPA pheomelanin is increased in nigral neuromelanin of Parkinson’s disease and it exacerbates alpha-synuclein neurotoxicity

Abstract

Objective: Neuromelanin (NM) of the human substantia nigra (SN) has long been proposed as a key factor contributing to dopaminergic neuron vulnerability in Parkinson's disease (PD). NM consists of pheomelanin and eumelanin moieties. Evidence supports that pheomelanin and eumelanin possess distinct chemical and biological characteristics. The present study aimed to investigate the relative composition and specific roles of pheomelanin and eumelanin moieties of NM in PD. Methods: Pheomelanin and eumelanin components of NM in postmortem SN tissues from patients with PD were assessed by chemical degradation methods and compared with those from control subjects as well as patients with Alzheimer's disease (AD). Additionally, synthetic pheomelanin and eumelanin were used to investigate their differential impacts on dopaminergic neuronal survival in a mouse model of PD overexpressing alpha-synuclein in the SN. Results: We identified increased L-3,4-dihydroxyphenylalanine (DOPA) pheomelanin and increased ratios of dopamine (DA) pheomelanin markers to DA in PD SN compared to the controls. Eumelanins derived from both DOPA and DA were reduced in PD group. Melanin markers were unaltered in AD SN compared to the controls. Furthermore, we showed exacerbated dopaminergic neurodegeneration by synthetic DOPA pheomelanin and attenuated DA deficit by synthetic DOPA eumelanin in an alpha-synuclein mouse model of PD. Conclusion: Our study provides insights into the different roles of pheomelanin and eumelanin moieties in PD pathophysiology. It forms a foundation for further investigations on pheomelanin and eumelanin individually as biomarkers and therapeutic targets for PD.