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.

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"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.

Oregon Health & Science University Apr 9 2025

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

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

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.

Source:

Oregon Health & Science University

Journal reference:

Arnold, M. R., et al. (2025). Alpha-synuclein regulates nucleolar DNA double-

strand break repair in melanoma. Science Advances.

doi.org/10.1126/sciadv.adq2519.