Protein Responsible for Parkinson’s Disease Also Drives Melanoma Progression

Researchers have uncovered a surprising mechanism linking Parkinson’s disease and melanoma, potentially explaining why people with one condition face higher risks of developing the other. The culprit: a protein called alpha-synuclein that plays dramatically different roles in neurons versus skin cancer cells.

The study, published in Science Advances, reveals that alpha-synuclein enhances DNA repair in melanoma cells, promoting cancer growth, while the same protein forms harmful aggregates in Parkinson’s disease that lead to neuronal death. In melanoma, alpha-synuclein remains in the cell nucleus, where it identifies DNA damage and recruits repair proteins, enabling uncontrolled cellular replication.

Vivek Unni, M.D., Ph.D.

This discovery builds on 2019 research from Oregon Health & Science University that first identified alpha-synuclein's role in DNA repair. The new findings, led by M.D./Ph.D. candidate Moriah Arnold and senior author Vivek Unni, M.D., Ph.D., show that in melanoma cells, this repair function is amplified rather than diminished, promoting tumor growth rather than cell death.

"When alpha-synuclein reaches a tipping point of abundance, it can no longer perform its normal function, and the neuron dies,” said Unni in an OHSU news release.

In the new study in melanoma cells, researchers found that alpha-synuclein accumulates within the nucleolus of melanoma cells, where it facilitates DNA double-strand break repair by recruiting a protein called 53BP1. When researchers deleted alpha-synuclein from melanoma cells, they observed increased DNA damage, slower repair processes, and reduced proliferation, migration, and invasion of cancer cells.

This contrasting behavior may shed new light on the long-recognized, yet poorly understood, overlap between Parkinson’s and melanoma. Epidemiological studies have consistently shown that people with Parkinson's face a higher risk of developing melanoma, while melanoma patients have an increased risk of developing Parkinson’s.

The findings suggest new treatment approaches targeting alpha-synuclein. For melanoma, reducing alpha-synuclein levels or altering its activity could limit DNA repair and induce cancer cell death. For Parkinson's, boosting DNA repair mechanisms might compensate for alpha-synuclein loss, particularly by enhancing 53BP1 recruitment.

Currently, no approved drugs specifically target alpha-synuclein, though several experimental therapies aimed at reducing its aggregation in the brain are in clinical trials for Parkinson’s disease. The OHSU team is now investigating whether alpha-synuclein interacts directly with DNA repair proteins and whether melanoma-specific factors that prevent alpha-synuclein aggregation might be used to stabilize the protein in neurons.

The research was supported by multiple organizations, including the National Institutes of Health, the Danish Cancer Society, the Melanoma Research Alliance and the Michael J. Fox Foundation.

Melanoma is an aggressive skin cancer that accounts for about 1% of all skin cancers, according to the American Cancer Society. This year, about 105,960 new cases of melanoma are expected to be diagnosed, and about 8,430 people are expected to die from melanoma.