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The melanoma‐linked “redhead” MC1R influences dopaminergic neuron survival
Author(s) -
Chen Xiqun,
Chen Hongxiang,
Cai Waijiao,
Maguire Michael,
Ya Bailiu,
Zuo Fuxing,
Logan Robert,
Li Hui,
Robinson Katey,
Vanderburg Charles R.,
Yu Yang,
Wang Yinsheng,
Fisher David E.,
Schwarzschild Michael A.
Publication year - 2017
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24852
Subject(s) - dopaminergic , mptp , melanocortin 1 receptor , neuroscience , melanocortin , substantia nigra , neurochemical , parkinson's disease , biology , dopamine , medicine , phenotype , disease , genetics , receptor , gene
Objective Individuals with Parkinson disease are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing Parkinson disease. Melanoma is strongly tied to red hair/fair skin, a phenotype of loss‐of‐function polymorphisms in the MC1R (melanocortin 1 receptor) gene. Loss‐of‐function variants of MC1R have also been linked to increased risk of Parkinson disease. The present study is to investigate the role of MC1R in dopaminergic neurons in vivo. Methods Genetic and pharmacological approaches were employed to manipulate MC1R, and nigrostriatal dopaminergic integrity was determined by comprehensive behavioral, neurochemical, and neuropathological measures. Results MC1R e/e mice, which carry an inactivating mutation of MC1R and mimic the human redhead phenotype, have compromised nigrostriatal dopaminergic neuronal integrity, and they are more susceptible to dopaminergic neuron toxins 6‐hydroxydopamine and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). Furthermore, a selective MC1R agonist protects against MPTP‐induced dopaminergic neurotoxicity. Interpretation Our findings reveal a protective role of MC1R in the nigrostriatal dopaminergic system, and they provide a rationale for MC1R as a potential therapeutic target for Parkinson disease. Together with its established role in melanoma, MC1R may represent a common pathogenic pathway for melanoma and Parkinson disease. Ann Neurol 2017;81:395–406