Common Red Hair Gene Variant Explains Association Between Deadly Skin Cancer and Parkinson's Disease

Highlights

• Melanoma risk is known to be increased in those who carry the red hair variant of the melanocortin 1 receptor (MC1R) gene, due to increased production of the lighter pigment called pheomelanin.
• This red-hair variant of melanoma-linked MC1R gene may also contribute to the known association between melanoma and Parkinson's disease (PD).
• The red-hair variant of MC1R gene, inactivates the gene and reduces the dopamine-producing neurons making them susceptible to damage, increasing risk for PD, over time.

A gene variant that produces red hair and fair skin in humans and in mice, which is known to increase the risk of the dangerous skin cancer melanoma, may also contribute to the known association between melanoma and Parkinson's disease. Although patients with Parkinson's disease have a reduced risk of developing most types of cancer, their higher risk of melanoma is well recognized, as is the increased risk of PD in patients with melanoma.

Researchers from the Massachusetts General Hospital (MGH) report that mice carrying the red hair variant of the melanocortin 1 receptor (MC1R) gene have reduced production of the neurotransmitter dopamine in the substantia nigra and are the dopamine-producing neurons are more sensitive to damage by toxic substances.

In Parkinson's disease (PD), dopamine-producing neurons in the substantia nigra are destroyed.

Several recent studies also have found evidence suggesting increased PD risk in individuals with red-hair-associated variants of MC1R.

The current study was designed to explore the potential role of the MC1R gene in PD and specifically in dopamine-producing neurons of the substantia nigra.

"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," says Xiqun Chen, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), lead and corresponding author of the report.

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"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 adds.

Red-Hair Gene Variant

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The skin pigmentation is determined by inherited variants of MC1R.

The most common variant causes greater production of the darker pigment called eumelanin and the red-hair-associated variant, increases production of the lighter pigment called pheomelanin. The red-hair variant inactivates the gene's function.

Negative effects of Pheomelanin:

• provides less protection from ultraviolet damage to the skin
• directly contribute to melanoma development

In the experiment, the researchers found that in mice that had common variant of MC1R, the gene is expressed in dopamine-producing neurons in the substantia nigra.

But in the red-haired mice, the gene function is inactivated because of the mutation and they had fewer dopamine-producing neurons. And as these mice aged, they developed a progressive decline in movement and a drop in dopamine levels.

They also were more sensitive to toxic substances known to damage dopamine-producing neurons and had indications of increased oxidative stress in brain structures adjacent to the substantia nigra.

Treating the mice with a substance that increases MC1R signaling reduced their susceptibility to a neurotoxin, which further supports the protective role for the gene's activity.

"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," says Chen, an assistant professor of Neurology at Harvard Medical School.

"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."

The paper is published in Annals of Neurology.

Reference

1. Xiqun Chen et . The melanoma-linked “redhead” MC1R influences dopaminergic neuron survival. Annals of Neurology; (2017) DOI: 10.1002/ana.24852

Source-Medindia