Linking Parkinson's Disease and Melanoma: Interplay Between α-Synuclein and Pmel17 Amyloid Formation

Parkinson's disease (PD) is a neurodegenerative disorder associated with the death of dopaminergic neurons within the substantia nigra of the brain. Melanoma is a cancer of melanocytes, pigmented cells that give rise to skin tone, hair, and eye color. Although these two diseases fundamentally differ, with PD leading to cell degeneration and melanoma leading to cell proliferation, epidemiological evidence has revealed a reciprocal relationship where patients with PD are more susceptible to melanoma and patients with melanoma are more susceptible to PD. The hallmark pathology observed in PD brains is intracellular inclusions, of which the primary component is proteinaceous α-synuclein (α-syn) amyloid fibrils. α-Syn also has been detected in cultured melanoma cells and tissues derived from patients with melanoma, where an inverse correlation exists between α-syn expression and pigmentation. Although this has led to the prevailing hypothesis that α-syn inhibits enzymes involved in melanin biosynthesis, we recently reported an alternative hypothesis in which α-syn interacts with and modulates the aggregation of Pmel17, a functional amyloid that serves as a scaffold for melanin biosynthesis. In this perspective, we review the literature describing the epidemiological and molecular connections between PD and melanoma, presenting both the prevailing hypothesis and our amyloid-centric hypothesis. We offer our views of the essential questions that remain unanswered to motivate future investigations. Understanding the behavior of α-syn in melanoma could not only provide novel approaches for treating melanoma but also could reveal insights into the role of α-syn in PD. © 2021 International Parkinson and Movement Disorder Society.