The melanoma‐linked “redhead” MC1R influences dopaminergic neuron survival

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Patients with Parkinson disease (PD), one of the most common neurodegenerative diseases, generally have reduced risk of developing almost all types of cancer, with one notable exception—melanoma, a malignant tumor of melanin‐producing cells in skin.1 A large number of epidemiological studies have reported that occurrence of melanoma is higher than expected among subjects with PD, and melanoma patients are reciprocally more likely to develop PD.1 Although well documented since the 1970s, mechanisms underlying this association between PD and melanoma remain largely unknown. Recent epidemiological studies further demonstrated the positive, bidirectional link not only in the patients themselves but also in their relatives,3 suggesting a possible genetic basis for the association between the two seemingly distinct conditions.
A cyclic adenosine monophosphate–stimulating G‐protein–coupled receptor (GPCR), melanocortin 1 receptor (MC1R) contributes to the regulation of skin physiology through the melanin synthetic pathway as well as pigmentation‐independent mechanisms.5 Loss‐of‐function variants of MC1R in humans are associated with red hair and fair skin and increased risk of developing melanoma.7 In mice, an inactivating mutation of MC1R (MC1R extension, e/e) with a phenotype analogous to red hair/fair skin in humans,9 results in impaired skin protection and is sufficient to enhance melanoma formation.10 Furthermore, MC1Re/e mice display greater oxidative damage in skin, suggesting an oxidative stress–mediated mechanism in carcinogenesis.11 In addition to skin melanocytes, other tissue and cell types that express MC1R include adrenal tissue, immunocytes, endothelial cells,12 and possibly human astrocytes13 and periaqueductal gray neurons,14 suggesting functions of MC1R extending beyond those in skin. In an analysis of 2 large prospective cohorts led by our epidemiologist collaborators, we found that red hair individuals and individuals homozygous for the red hair–associated Arg151Cys allele of Cys were associated with an increased risk for PD.15 The association was substantiated by another study linking PD with an alternative red hair MC1R variant in an independent cohort.16 Although other studies17 did not replicate a significant MC1R–PD association, which may be attributable to technical or population differences across studies,21 MC1R has nevertheless emerged as having a potential role at the interface of melanoma and PD.
To explore such a role of MC1R in dopaminergic neurons and therefore a biological basis for the PD–melanoma link, we first assessed expression of MC1R in dopaminergic neurons of the substantia nigra (SN) in the mouse brain. Redhead MC1Re/e mice were then employed to investigate effects of MC1R inactivation on the nigrostriatal dopaminergic system under basal conditions and in well‐established 6‐hydroxydopamine (6‐OHDA) and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) models of PD.22 Furthermore, the neuroprotective potential of MC1R stimulation in an MPTP model was explored using a potent, specific MC1R agonist 1‐(1‐[3‐methyl‐L‐histidyl‐O‐methyl‐D‐tyrosyl]‐4‐phenyl‐4‐piperidinyl)‐1‐butanone (BMS‐470539).

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