Research from a team of investigators at Oregon Health & Science University (OHSU) has found that alpha-synuclein (αSyn), a protein long associated with neurodegeneration in Parkinson’s disease, also plays a direct role in the development of melanoma by enhancing DNA repair in cancer cells. The research provides a new understanding of αSyn’s dual role and context to long-standing observations that people with Parkinson’s disease are significantly more likely to develop melanoma, and vice versa.
“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,” the researchers wrote in their study which was published in Science Advances.
This dual behavior of αSyn stems from its distinct roles in different cell types. Previous work from the OSHU lab of senior author Vivek Unni, MD, PhD, in 2019 demonstrated αSyn’s role in DNA double-strand break (DSB) repair in neurons. The new research, led by OHSU MD/PhD candidate Moriah Arnold, revealed that in melanoma cells, αSyn’s DNA repair function is not diminished but amplified, which promotes tumor growth.
To explore this newly uncovered connection, the researchers analyzed melanoma cell lines and tumor samples and found that αSyn was highly enriched in the nucleolus, the region within the cell nucleus responsible for producing ribosomes and known to be prone to DNA damage due to its high transcriptional activity. Upon inducing DNA breaks specifically in the nucleolar ribosomal DNA (rDNA), they observed a marked increase in αSyn at damage sites, where it facilitated recruitment of the DNA repair protein 53BP1.
When αSyn was genetically deleted, melanoma cells showed more DNA damage, slower repair, and reduced proliferation, migration, and invasion.
“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,” the researchers wrote.
This activity contrasts with αSyn’s role in neurons, where an overabundance of the protein leads it to mislocalize from the nucleus into cytoplasmic aggregates known as Lewy bodies, contributing to neuronal 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.”
In cancer cells, however, αSyn remains soluble and nuclear, enhancing DNA repair and promoting cell survival. This might be the result of melanoma cells expressing factors that prevent αSyn aggregation, allowing it to remain functional. The team’s transcriptomic analysis showed that αSyn deletion significantly altered gene expression linked to DNA damage response. Notably, the gene ATF3, known to be activated by DNA damage and is a suppressor of cell growth, was upregulated 30-fold in αSyn-deficient cells. Other genes involved in chromatin remodeling and DSB repair, including HMGA1 and HMGA2, were also upregulated.
These findings suggest that therapies modulating αSyn’s nuclear function could influence the progression of both PD and melanoma. One approach being explored is reducing αSyn levels or altering its activity in melanoma to limit DNA repair and induce cancer cell death. Conversely, in Parkinson’s, the strategy may involve boosting DNA repair mechanisms, such as enhancing 53BP1 recruitment, to compensate for αSyn loss.
Currently, no approved drugs specifically target αSyn for the treatment of either Parkinson’s disease or cancer. However, several experimental therapies aimed at reducing αSyn aggregation in the brain are in clinical trials for PD. The new findings suggest that similar therapeutic principles might be adapted for melanoma, albeit with the opposite objective of reducing αSyn and αSyn function instead of preserving it.
The OSHU team now plans to test whether αSyn interacts directly with DNA repair proteins like MDC1 or 53BP1 and whether disrupting these interactions could be a viable therapeutic strategy. The team is also interested in exploring whether melanoma-specific factors that prevent αSyn aggregation might be used to stabilize the protein in neurons.
