Social Science Research Network | 2021
Melanocortin 1 Receptor Activation Protects Against Alpha-Synuclein Pathologies in Models of Parkinson’s Disease
Abstract
Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R), hair color, and risk of Parkinson’s disease (PD). We previously showed that MC1R signaling is required for nigrostriatal dopaminergic neuron maintenance in adult mice. Here, we report exacerbated synucleinopathies induced by targeted expression of α-synuclein (αSyn) in the nigrostriatal pathway in MC1R mutant mice, which were accompanied by neuroinflammation and altered nuclear factor erythroid 2-related factor 2 (Nrf2) response. The resulting exacerbated dopaminergic neurotoxicity was reversed by humanMC1R transgene. Additionally, pharmacological MC1R activation was neuroprotective against αSyn-induced dopaminergic neurotoxicity. Further in vitro experiments showed that Nrf2 was a necessary downstream mediator of MC1R activation. Finally, MC1R was present in dopaminergic neurons in the human substantia nigra and was reduced in PD patients. Our study supports an interaction between MC1R and αSyn that is mediated by neuronal MC1R through Nrf2. It provides evidence for MC1R as a therapeutic target and a rationale for development of MC1R-activating strategies in PD.