Common genetic marker associated with faster Parkinson’s disease progression

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 Michael J. Fox Foundation’s landmark study, Parkinson's Precision Medicine 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.

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Xiqun Chen, MD, PhD