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 DNA damage, may cause skin cancer cells to grow out of control by overperforming the same job. While in neurons this protein can trigger cell death, in melanoma it enables unchecked replication — showing how one molecule can drive two very different diseases. Scientists now hope this duality opens the door to new drugs that could fight both conditions at once.
Protein Linking Parkinson’s and Melanoma Discovered
A small protein known for its role in Parkinson’s disease may also play a key part in driving melanoma, a serious form of skin cancer, according to new research led by Oregon Health & Science University.
The study, published today (April 9) in Science Advances, highlights the protein alpha-synuclein as a potential target for treating or preventing both diseases. The research suggests that alpha-synuclein plays a crucial role in regulating how cells function, and that its behavior can either protect cells or contribute to disease.
“Developing drugs that target alpha-synuclein may be useful in both diseases,” said senior author Vivek Unni, M.D., Ph.D., an associate professor of neurology in the OHSU School of Medicine.
Past Discoveries Inform Present Breakthroughs
This new discovery builds on 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” by Moriah R. Arnold, Gabriel M. Cohn, Kezia Catharina Oxe, Somarr N. Elliott, Cynthia Moore, Allison May Zhou, Peter V. Laraia, Sahar Shekoohi, Dillon Brownell, Rosalie C. Sears, Randall L. Woltjer, Charles K. Meshul, Stephan N. Witt, Dorthe H. Larsen and Vivek K. Unni, 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 National Institutes of Health, Awards F30AG082406, R01NS102227, P30NS061800 and P30CA065823; the Danish Cancer Society award R302-A17506; the Melanoma Research Alliance, the Michael J. Fox Foundation, the Kuni Foundation; a Medical Student Research Award of the Melanoma Research Foundation; and a Ph.D. Scholar COVID-relief Award of the OHSU Knight Cancer Institute.
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