Summary: A new study reveals that the protein alpha-synuclein, known for its role in Parkinson’s disease, also contributes to the development of melanoma by promoting excessive DNA repair and cell proliferation. While in neurons, excess alpha-synuclein leads to cell death, in melanoma cells it enables uncontrolled growth by recruiting repair proteins to DNA breaks.
This dual role highlights the complex nature of alpha-synuclein and suggests new therapeutic targets for both diseases. Researchers now aim to modulate this protein’s function to either curb cancer growth or restore protective DNA repair in neurons.
Key Facts:
- Dual Role of Alpha-Synuclein: In Parkinson’s, it exits the nucleus and forms harmful clumps; in melanoma, it remains in the nucleus and over-repairs DNA.
- Cancer Mechanism: In melanoma cells, alpha-synuclein boosts the recruitment of repair protein 53BP1, promoting cell survival and proliferation.
- Therapeutic Potential: Drugs that adjust alpha-synuclein function could offer new treatments for both Parkinson’s disease and melanoma.
Source: Oregon Health and Science University
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,” 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.
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.
Funding: 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.
About this genetics, Parkinson’s, and Cancer research news
Author: Erik Robinson
Source: Oregon Health and Science University
Contact: Erik Robinson – Oregon Health and Science University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma” by Vivek Unni, et al. Science Advances
Abstract
Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma
Although an increased risk of the skin cancer melanoma in people with Parkinson’s disease (PD) has been shown in multiple studies, the mechanisms involved are poorly understood, but increased expression of the PD-associated protein alpha-synuclein (αSyn) in melanoma cells may be important.
Our previous work suggests that αSyn can facilitate DNA double-strand break (DSB) repair, promoting genomic stability. We now show that αSyn is preferentially enriched within the nucleolus in melanoma, where it colocalizes with DNA damage markers and DSBs.
Inducing DSBs specifically within nucleolar ribosomal DNA (rDNA) increases αSyn levels near sites of damage. αSyn knockout increases DNA damage within the nucleolus at baseline, after specific rDNA DSB induction, and prolongs the rate of recovery from this induced damage.
αSyn is important downstream of ataxia-telangiectasia–mutated signaling to facilitate MDC1-mediated 53BP1 recruitment to DSBs, reducing micronuclei formation and promoting cellular proliferation, migration, and invasion.
