A new study by investigators from the Mass General Brigham Neuroscience Institute has identified common genetic variants in the MC1R gene as markers of faster motor decline in people with Parkinson's disease (PD). The findings, published in JAMA Neurology , suggest that MC1R could help identify a large subgroup of patients at risk for more rapid disease progression and open a new avenue for drug development.
"MC1R variants were common among individuals in our study and associated with substantially faster disease progression," said Xiqun Chen, MD, PhD , senior author and investigator with the Mass General Brigham Neuroscience Institute. "This finding suggests that a simple genetic test could help improve prognostic assessment and clinical trial design for a large proportion of patients. Importantly, MC1R is a druggable target, and drugs that activate this pathway have shown protective effects in preclinical models of PD."
PD is a neurodegenerative disease that involves the progressive loss of dopamine-producing neurons in the brain, manifesting in tremor, slowness of movement, stiffness, and difficulty with balance and coordination. MC1R is the gene responsible for hair and skin pigmentation, best known for its link to red hair and melanoma.
While red hair is rare, variants that partially reduce MC1R function are far more prevalent — carried by more than 60% of patients with PD who are of European descent. MC1R also regulates how cells, including the dopamine-producing neurons lost in PD, respond to oxidative stress.
The new study used longitudinal data from the Parkinson's Progressive Markers Initiative (PPMI), an international cohort with up to 12 years of follow-up. The primary analysis included 383 participants with sporadic Parkinson's disease, classified according to whether they carried an MC1R loss-of-function variant. Among patients with PD who did not have a known genetic mutation associated with the disease, those with MC1R loss-of-function variants experienced approximately 30% faster motor decline than non-carriers. Further, the effect was allele dose-dependent: compared with non-carriers, individuals carrying two copies of a loss-of-function variant experienced a 63% faster rate of motor decline, versus 27% among those carrying one copy.
Their findings were then replicated in a separate pooled clinical trial-based cohort of 587 patients. In this cohort, carriers experienced approximately 50% faster motor decline. In a small group of patients with early signs of PD who had not yet received a clinical diagnosis, variant carriers were more than four times as likely to develop PD.
"What stands out to me is the consistency of this association in an independent replication cohort. The results hold up in different cohorts across different stages of disease we examined: in individuals with prodromal features not yet diagnosed with PD, in early untreated patients, and in those already on dopaminergic therapy. That kind of convergence, combined with the dose-dependent effect, is compelling," said Jackson Schumacher, BS, co-first author and research associate at the Mass General Brigham Neuroscience Institute.
This study extends the team's previous work demonstrating that MC1R is at the intersection between melanoma and Parkinson's disease. The authors conclude that while further research is needed, these clinical findings together with the team's preclinical evidence that existing MC1R agonists are neuroprotective provide a rationale for investigating MC1R-based therapies in Parkinson's disease.
Authorship: In addition to Chen and Schumacher, Mass General Brigham authors include Xinyuan Zhang, Eric A. Macklin, and Michael A. Schwarzschild. Additional authors include Jian Wang, Johannes M. Dijkstra, Hirohisa Watanabe, Xiang Gao, and Marianna Cortese.
Funding: This research was funded in part by Aligning Science Across Parkinson's (grants ASAP-000312 and MJFF-028544) through the Michael J. Fox Foundation for Parkinson's Research (MJFF) and by the National Institutes of Health through the National Institute of Neurological Disorders and Stroke (grant R01NS102735).
Paper cited: Schumacher, JG et al. "Common MC1R variants and Parkinson disease progression" JAMA Neurology DOI: 10.1001/jamaneurol.2026.2998
