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. .