A tiny protein at the center of Parkinson’s disease also plays a surprising role in melanoma, a dangerous skin cancer.
New research reveals that alpha-synuclein, which helps protect brain cells from earlier work by Unni and colleagues in 2019, which showed that alpha-synuclein helps repair double-strand breaks in the DNA of brain cells, or neurons. This repair function appears to be essential for cell survival. In Parkinson’s and Lewy body dementia, however, the protein leaves the nucleus and forms harmful clumps, known as Lewy bodies, contributing to neuron death.
The new study, conducted in melanoma cells and led by OHSU M.D./Ph.D. student Moriah Arnold, B.A., finds the opposite effect with respect to melanoma.
In melanoma, researchers found that alpha-synuclein does its job too well — allowing cells to proliferate uncontrollably as cancer.
Runaway Repair Process Fuels Cancer
“Skin cells are constantly growing and dying and being replaced. That’s normal,” Unni said. “The problem comes when the cells that should be dying don’t.”
Researchers found that alpha-synuclein in melanomas don’t seem to leave the nucleus and aggregate as they do with neurons in Parkinson’s. Instead, the opposite occurs. They increase in the nucleus and perform their function too well within the nucleolus of each melanoma cell’s nucleus: identifying double strand breaks in DNA and then recruiting a different type of protein, known as 53BP1, to repair them.
This can lead to runaway cellular replication — cancer.
Why More Alpha-Synuclein Can Kill Neurons
Counterintuitively, Unni said, a similar increase in alpha-synuclein leads to cellular death in Parkinson’s. Why? In neurons as opposed to skin cells, an overabundance of alpha-synuclein seems to pull them out of the cell’s nucleus into clusters forming in the cytoplasm surrounding the nucleus, Unni said. This, in turn, leads to cellular death.
“A neuron has to live the whole life of a person,” Unni said. “When alpha-synuclein reaches a tipping point of abundance, it can longer perform its normal function and the neuron dies.”
Toward New Treatments for Two Diseases
The study suggests it may be possible to develop a drug that lowers the level of alpha-synuclein or modulates its function to treat melanoma, he said. Alternatively, he said his research is now exploring other avenues to boost the recruitment of the binding protein 53BP1 to replace the function of alpha-synuclein as a possible treatment for Parkinson’s.
“This provides a framework for understanding the link between (Parkinson’s disease) and melanoma, and offers potential therapeutic targets in melanoma that are focused on reducing aSyn-mediated nucleolar double strand break repair,” the authors conclude.
Reference: “Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma” 9 April 2025, Science Advances.
DOI: 10.1126/sciadv.adq2519
Research was supported by the National Institute on Aging, National Institute of Neurological Disorders & Stroke, and National Cancer Center, of the Adblock test (Why?)
