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

Abstract

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 MC1Re/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.

Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease

“…Supporting this concept: (1) PD patients have an increased risk of developing cutaneous melanoma and, reciprocally, patients with cutaneous melanoma have an increased risk of developing PD 91 ; (2) similar to neurons, cutaneous melanocytes derive from pluripotent neural crest cells and their maturation is influenced by the same signaling molecules that play a role in central and peripheral nervous tissue 92 ; (3) loss-of-function variants of the melanocortin 1 receptor gene, which are associated with red hair and fair skin, are linked to an increased risk of both cutaneous melanoma and PD 93,94 ; (4) genetically modified mice carrying an inactivating mutation of melanocortin 1 receptor mimicking the human redhead phenotype have compromised nigrostriatal dopaminergic neuronal integrity and are more susceptible to dopaminergic parkinsonian neurotoxins. 95…”

Odd correlation: Parkinson’s disease and melanoma. What is the possible link?

“…In red-haired people, the thinning or even lack of eumelanin in neuromelanin may determine the sensitivity of dopaminergic neurons to neurodegenerative processes associated with oxidative reactions or sensitivity to dopaminergic toxins, i.e. 6-OHDA or MPTP [30].…”

“…In the substantia nigra neurons in mice, the expression of MC1R is localised in the cytoplasm and overlaps the expression of tyrosine hydroxylase involved in dopamine synthesis, which may indicate their functional association [30]. And it seems to be so because the mouse model has shown that the "red-haired" variant of the MC1R gene reduces the production of dopamine in the substantia nigra and increases the sensitivity of brain cells to harmful dopaminergic substances.…”

Increased calcidiol level in redhaired people: Could redheadedness be an adaptation to temperate climate?

“…It has been speculated that these alleles spread due to sexual selection, in particular by selection in favor of a rare phenotype (Frost, 2006; Frost, Kleisner, & Flegr, 2017). Many anecdotal observations (Chen et al, 2017; Liem, Hollensead, Joiner, & Sessler, 2006; Missmer et al, 2006; Somigliana et al, 2010; Tell-Marti et al, 2015) and one systematic largescale study (Frost et al, 2017) reveal that redhaired persons, especially women, tend to suffer from various symptoms of impaired health and from a higher frequency of certain diseases, including colorectal, cervical, uterine, and ovarian cancer than their non-redhaired peers. It has been suggested that the resulting selection against redhaired individuals counterbalances the positive sexual selection in favor of redhaired women, thereby maintaining the corresponding alleles at a low but stable frequency (Frost et al, 2017).…”