“Ginger” Gene Underlies Parkinson’s-Melanoma Link
The association between melanoma and Parkinson’s disease (PD) has been an elusive phenomenon for some years. Turns out, a gene variant that produces red hair and fair skin in humans and in mice, which increases the risk of the dangerous skin cancer melanoma, may also contribute to the melanoma–PD association. Now, investigators from the Massachusetts General Hospital (MGH) have published their findings that show mice carrying the red hair variant of the melanocortin 1 receptor (MC1R) gene have reduced production of the neurotransmitter dopamine in the substantia nigra—the region of the brain where dopamine-producing neurons are destroyed in Parkinson's disease (PD)—and are more susceptible to toxins known to damage those neurons.
The results of this new study were published recently in the Annals of Neurology in an article entitled “The Melanoma-Linked “Redhead” MC1R Influences Dopaminergic Neuron Survival.”
"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," explained lead study investigator Xiqun Chen, M.D., Ph.D., assistant professor of neurology at Harvard Medical School and assistant in neuroscience at the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND). "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."
Interestingly, while patients with PD have a reduced risk of developing most types of cancer, their higher-than-expected risk of melanoma has not gone unnoticed, as is the increased risk of PD in patients with melanoma. Inherited variants of the MC1R gene determine skin pigmentation, with the most common form leading to greater production of the darker pigment called eumelanin and the red-hair-associated variant, which inactivates the gene's function, increasing production of the lighter pigment called pheomelanin. Not only does pheomelanin provide less protection from ultraviolet damage to the skin than does eumelanin, but a previous study found it also may directly contribute to melanoma development.
Several recent studies found evidence suggesting increased PD risk in individuals with red hair-associated variants of MC1R, so the current study was designed to explore that potential role of the gene in PD and specifically in dopamine-producing neurons of the substantia nigra. To that end, the investigators showed that in mice with the common form of MC1R, the gene was expressed in dopamine-producing neurons of the substantia nigra. The red-haired mice in which the gene is inactivated because of a mutation were found to have fewer dopamine-producing neurons and as they aged developed a progressive decline in movement and a drop in dopamine levels.
Additionally, the variant gene neurons were more sensitive to toxic substances known to damage dopamine-producing neurons and had indications of increased oxidative stress—which previous work implied was involved in pheomelanin-associated melanoma risk—in brain structures adjacent to the substantia nigra. Treatment with a substance that increases MC1R signaling reduced the susceptibility of mice with the common variant to a neurotoxin, further supporting a protective role for the gene's activity.
"Since MC1R regulates pigmentation and red hair is a shared risk factor for both melanoma and PD, it is possible that, in both conditions, MC1R's role involves pigmentation and related oxidative stress," Dr. Chen concluded. "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 PD."
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