# MC1R basis of melanoma-Parkinson's link and neuroprotective potential of MC1R

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $351,865

## Abstract

Project Summary/Abstract
Parkinson's disease (PD) patients generally are at lower risk of developing cancers, with one notable exception –
melanoma. Individuals with PD are more likely to develop melanoma, and melanoma patients are reciprocally at
higher risk of developing PD. This bidirectional link has been observed not only in patients themselves but also in
their relatives, suggesting shared biological components of the two seemingly disparate processes. Melanoma is
strongly tied to red hair/fair skin, the phenotype of loss-of-function polymorphisms in the melanocortin 1 receptor
gene (MC1R). We have previously reported greater PD risk in individuals with red hair color and individuals
carrying a redhead MC1R variant. Normally black (C57Bl/6) mice carrying an inactivating mutation of MC1R
(MC1Re/e mice) mimic redhead humans, as they display red/yellow pheomelanin pigmentation and
pheomelanin-dependent oxidative skin damage and melanoma predisposition. These redhead mice also exhibit
oxidative brain damage and dopaminergic deficiency under basal conditions and exacerbated dopaminergic
toxicity in models of PD including α-synuclein (α-syn). MC1R is expressed in dopaminergic neurons of the mouse
substantia nigra. The presence of MC1R has also been preliminarily demonstrated in the substantia nigra of the
human brain, with reduced signal in sporadic PD patients that correlates to loss of dopaminergic neurons.
Further, higher PD-associated mortality among redhead individuals has been preliminarily demonstrated in
human cohorts. The overall goal of this interdisciplinary project is to further elucidate role of the melanoma-linked
MC1R in PD and neuroprotective potential of targeting MC1R by studying animal models and human populations
in parallel via three Specific Aims (SAs). SA1 will determine whether red pigmentation is responsible for the
redhead dopaminergic deficit and whether MC1R in catecholaminergic cells is required for nigrostriatal
dopaminergic integrity. SA2 will determine whether MC1R activation by existing MC1R agonists protects
against α-syn neurotoxicity and whether the protection is MC1R-specific. SA3 will analyze whether redhair and
melanoma risk MC1R variants are associated with increased risk of developing PD in healthy populations and
whether the same variants are associated with faster clinical progression in those who have already been
diagnosed with PD. Built on the strength of epidemiological and biological evidence and backed by exceptional
expertise across disciplines, the proposed study is expected to establish the biological plausibility of a causal
basis for MC1R (and pheomelanin) and PD and therefore to provide insight into PD-melanoma association. Its
findings will be of high translational significance with the potential for major impact on PD therapeutics as well as
on our understanding of the epidemiology and pathophysiology of PD.
.

## Key facts

- **NIH application ID:** 9891118
- **Project number:** 5R01NS102735-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Xiqun Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,865
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891118

## Citation

> US National Institutes of Health, RePORTER application 9891118, MC1R basis of melanoma-Parkinson's link and neuroprotective potential of MC1R (5R01NS102735-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891118. Licensed CC0.

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