| First Author | Cai W | Year | 2022 |
| Journal | Mol Neurodegener | Volume | 17 |
| Issue | 1 | Pages | 16 |
| PubMed ID | 35197079 | Mgi Jnum | J:322646 |
| Mgi Id | MGI:6885003 | Doi | 10.1186/s13024-022-00520-4 |
| Citation | Cai W, et al. (2022) Melanocortin 1 receptor activation protects against alpha-synuclein pathologies in models of Parkinson's disease. Mol Neurodegener 17(1):16 |
| abstractText | BACKGROUND: Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R) and risk of Parkinson's disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neurotoxicity induced by alpha-synuclein (alphaSyn), a key player in PD genetics and pathogenesis. METHODS: Nigral dopaminergic neuron toxicity induced by local overexpression of aSyn was assessed in mice that have an inactivating mutation of MC1R, overexpress its wild-type transgene, or were treated with MC1R agonists. The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in MC1R-mediated protection against alphaSyn was characterized in vitro. Furthermore, MC1R expression was determined in human postmortem midbrain from patients with PD and unaffected subjects. RESULTS: Targeted expression of alphaSyn in the nigrostriatal pathway induced exacerbated synuclein pathologies in MC1R mutant mice, which were accompanied by neuroinflammation and altered Nrf2 responses, and reversed by the human MC1R transgene. Two MC1R agonists were neuroprotective against alphaSyn-induced dopaminergic neurotoxicity. In vitro experiments showed that Nrf2 was a necessary mediator of MC1R effects. Lastly, MC1R was present in dopaminergic neurons in the human substantia nigra and appeared to be reduced at the tissue level in PD patients. CONCLUSION: Our study supports an interaction between MC1R and alphaSyn that can be mediated by neuronal MC1R possibly through Nrf2. It provides evidence for MC1R as a therapeutic target and a rationale for development of MC1R-activating strategies for PD. |
