Researchers have found that the melanocortin 1 receptor (MC1R) gene is needed to protect neurons from damaging toxins and for the production of dopamine in the brain, two characteristics that are essential for prevention of Parkinson’s disease (PD). Because MC1R variants are associated with melanoma development, these results suggest that MC1R may be the missing link between PD and malignant skin cancer.
The study “The melanoma-linked “redhead” MC1R influences dopaminergic neuron survival” was published in the journal Annals of Neurology.
“This study is the first to show direct influences of the melanoma-linked MC1R gene on dopaminergic neurons in the brain and may provide evidence for targeting MC1R as a novel therapeutic strategy for PD,” Xiqun Chen, MD, PhD, study lead author, said in a press release.
Several studies have demonstrated that patients who suffer from PD are at higher risk of malignant skin cancer. Similarly, melanoma patients also were reported to be more likely to develop PD. Although the link between the two diseases is not known, studies have suggested the answer might lay in the patients’ genetics.
The MC1R gene is responsible for skin and hair pigmentation. A known variation of this gene gives rise to the relatively uncommon red hair and fair skin, due to the production of a lighter pigmentation, called pheomelanin. Those who carry this “mutated” form of MC1R are less protected from ultraviolet radiation damage, which is associated with a higher risk for melanoma development.
Recent evidence has suggested that people with red-hair-associated variants of MC1R are more prone to develop PD. To better understand the role of MC1R in PD, researchers at Massachusetts General Hospital analyzed the neurological response of animal models expressing the red-hair variant of the MC1R gene.
“Since MC1R regulates pigmentation and red hair is a shared risk factor for both melanoma and Parkinson’s disease, it is possible that, in both conditions, MC1R’s role involves pigmentation and related oxidative stress,” said Chen.
The researchers found that animals with the common MC1R form expressed the gene in a specific part of the brain, called the substantia nigra, and by a specific group of dopamine-producing neurons. Both the substantia nigra and the dopamine produced by neurons have been associated with PD development in humans, and are responsible for the control and coordination of movement.
When they looked into red-hair mice, they observed they had fewer dopamine-producing neurons. The mice also developed a progressive decline in movement and drop in dopamine production as they aged.
These mice also were more sensitive to substances that could damage dopamine-producing neurons. The authors reported that the brain structures close to the substantia nigra present increased levels damaging oxidative stress. This last feature had been previously associated to the increased risk to melanoma due to pheomelanin production.
Using a drug that increased MC1R signaling, reproducing its normal activity, the team was able to overcome increased sensitivity of the brain neurons to toxicity. This suggested that the MC1R gene could have a protective role against neuron damage and degeneration.
“Our findings suggest further investigation into the potential of MC1R-activating agents as novel neuroprotective therapies for PD, and together with epidemiological evidence, may offer information that could guide those carrying MC1R variants to seek advice from dermatologists or neurologists about their personal risk for melanoma and Parkinson’s disease,” Chen said.
“It also forms a foundation for further interdisciplinary investigations into the dual role of this gene in tumorigenesis within melanocytes — the pigment cells in which melanoma develops — and the degeneration of dopaminergic neurons, improving our understanding of why and how melanoma and Parkinson’s disease are linked,” Chen added.
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