While Parkinson’s disease (PD), a neurodegenerative disorder leading to cell death, and melanoma, a cancer of melanocytes leading to uncontrolled cell growth, fundamentally differ, a unique connection between the two diseases has been observed for nearly 50 years. Epidemiological studies have shown that melanoma occurs 2–6 times more frequently in PD patients as compared to the general population, and that individuals with melanoma are more susceptible to PD. α-Synuclein (α-syn), the hallmark pathological protein observed in Lewy bodies from brains of PD patients, is elevated in melanoma, suggesting that α-syn could be a molecular link between the two diseases. A consistent observation is that α-syn expression is inversely correlated to the amount of pigment or melanin found in melanoma cells. Currently, little is known about the role that α-syn plays in melanoma progression. We propose a novel hypothesis that there is an amyloid link between α-syn and Pmel (pre-melanosomal protein), a functional amyloid that promotes melanin biosynthesis in melanocytes. Using confocal immunofluorescence microscopy and western blotting of SK-MEL 28 human melanoma cells, we recently reported that endogenous α-syn and Pmel compartmentalize within the melanosome, the organelle in which melanin is synthesized, and that α-syn fibrils stimulate the aggregation of Pmel repeat domain (RPT) <i>in vitro</i>. Here, we further define this interaction by showing that soluble (disordered) α-syn acts as an inhibitor of RPT aggregation in a concentration-dependent manner, with an estimated half maximum inhibition (IC<sub>50</sub>) of 200 nM. Using two different truncated α-syn constructs spanning N- and C-terminal residues, 1–60 and 66–140, we show that the amphipathic N-terminus of α-syn alone can inhibit RPT aggregation, while the latter half has no impact. Taken together, these results support our hypothesis that α-syn, a pathogenic amyloid, infiltrates and disrupts conventional Pmel amyloid formation, thus leading to the modulation of melanin production, the biological function of Pmel.

Defining an amyloid link between Parkinson’s disease and melanoma

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.