期刊
ANNALS OF NEUROLOGY
卷 81, 期 3, 页码 395-406出版社
WILEY
DOI: 10.1002/ana.24852
关键词
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资金
- National Institute of Neurological Disorders and Stroke [1R21NS090246-01A1, K24NS060991]
- National Natural Science Foundation of China [81471293]
- RJG Foundation [2011D004473]
- Michael J. Fox Foundation [9908]
- Milstein Medical Asian American Partnership Foundation
- US Department of Defense [W81XWH-11-1-0150]
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.
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