A small protein long known for its role in neurodegeneration now appears to contribute to a completely different disease—melanoma. Researchers at Oregon Health & Science University (OHSU) have discovered that the protein alpha-synuclein, implicated in Parkinson’s disease, also drives the development of this aggressive form of skin cancer.
Dual Roles of Alpha-Synuclein in Cells
In a new study published in Science Advances, scientists revealed that alpha-synuclein regulates key cellular functions, with drastically different outcomes in neurons versus skin cells. This groundbreaking research opens the door to potential new drug therapies that could simultaneously target both Parkinson’s disease and melanoma.
“Developing drugs that target alpha-synuclein may be useful in both diseases,” said senior author Dr. Vivek Unni, associate professor of neurology at the OHSU School of Medicine.
From Protecting Neurons to Promoting Cancer
Previously, Unni’s team showed in a 2019 study that alpha-synuclein plays a critical role in neurons by repairing double-strand DNA breaks, helping to prevent cell death. However, when alpha-synuclein exits the nucleus and forms toxic clumps—known as Lewy bodies—it contributes to the neuron loss seen in Parkinson’s disease and Lewy body dementia.
In the latest study, OHSU M.D./Ph.D. student Moriah Arnold led research that reveals an opposite effect in melanoma cells. Here, alpha-synuclein remains within the cell nucleus and performs its repair function too efficiently.
How Alpha-Synuclein Fuels Melanoma Growth
Unlike neurons, skin cells are designed to grow, die, and renew constantly. Yet, in melanoma cells, alpha-synuclein prevents damaged cells from dying. It identifies double-strand DNA breaks and recruits another protein—53BP1—to rapidly repair them. As a result, faulty cells evade death and continue multiplying, fueling cancer growth.
“The problem comes when the cells that should be dying don’t,” said Unni.
Contrasting Behavior in Neurons and Skin Cells
Interestingly, the same protein that encourages cancer growth in skin cells triggers cell death in neurons. In neurons, high levels of alpha-synuclein pull the protein out of the nucleus. It then forms clumps in the surrounding cytoplasm, disrupting its DNA repair function and leading to cell death.
“A neuron has to live the whole life of a person,” Unni explained. “When alpha-synuclein reaches a tipping point of abundance, it can no longer perform its normal function and the neuron dies.”
New Avenues for Treatment
As reported by medicalxpress, these findings highlight alpha-synuclein as a key player in two very different diseases. By modulating the level or function of this protein, scientists may develop new therapies for both melanoma and Parkinson’s disease. Unni’s team is now investigating ways to either reduce alpha-synuclein activity in melanoma or enhance the function of the 53BP1 protein in neurons as an alternative therapeutic strategy.
Conclusion
“This provides a framework for understanding the link between Parkinson’s disease and melanoma,” the authors conclude, “and offers potential therapeutic targets in melanoma that are focused on reducing alpha-synuclein-mediated nucleolar double-strand break repair.”