Protein linked to Parkinson's also found to drive melanoma growth

A small protein involved in neurodegeneration leading to Parkinson's disease also drives a type of skin cancer known as melanoma, new research led by Oregon Health & Science University finds.

The study, published today in the journal Science Advances, suggests new avenues for drug development to reduce the risk of developing both Parkinson's and skin cancer by targeting the alpha-synuclein protein, which appears to have a critical role in regulating cellular functions.

"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.

The finding builds on a previous discovery by Unni and colleagues published in 2019 that found alpha-synuclein helps to perform a critical function by repairing double strand breaks in the DNA of brain cells known as neurons. They believe this function is crucial in preventing cell death, which occurs when alpha-synuclein exits the cell's nucleus and instead forms clumps known as Lewy bodies in Parkinson's and Lewy body dementia.

The new study, conducted in melanoma cells and led by OHSU M.D./Ph.D. student Moriah Arnold, B.A., Ph.D., finds the opposite effect in respect to melanoma.

In melanoma, researchers found that alpha-synuclein does its job too well - allowing cells to proliferate uncontrollably as cancer.

Skin cells are constantly growing and dying and being replaced. That's normal. The problem comes when the cells that should be dying don't."

Vivek Unni, M.D., Ph.D., associate professor of neurology, OHSU School of Medicine

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.

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 no longer perform its normal function and the neuron dies."

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.