Parkinson's Disease and Melanoma: The Same Protein May Hold the Key to Curing Both

The alpha-synuclein protein, known to be involved in Parkinson’s disease, can also promote the development of melanoma, a serious type of skin cancer. In neurons, excess levels of this protein cause damage and lead to cell death, but in melanoma cells, it helps repair DNA and causes cells to grow out of control. Scientists now believe that understanding this behavior could help create new treatments to combat both Parkinson’s and melanoma.

Several studies have shown that people with Parkinson’s disease (PD) have a higher risk of developing melanoma, an aggressive type of skin cancer. However, it was not yet fully understood why these two very different diseases were related.

Now, new research is beginning to reveal a possible explanation, involving a protein called alpha-synuclein (αSyn).

In previous studies, scientists discovered that alpha-synuclein plays an important role in brain cells: it helps repair severe DNA damage, known as double-strand breaks. This damage can be fatal to the cell if it is not corrected, so the repair function of alpha-synuclein is essential to maintain the health of neurons.

In the new study, researchers from Oregon Health and Science University, USA, observed the behavior of alpha-synuclein in melanoma cells. They found that, in these skin cancer cells, alpha-synuclein is also very active, but in this case, it ends up helping the cancer to grow.

The research showed that alpha-synuclein accumulates in the nucleolus (a structure inside the cell nucleus where ribosome components are produced) and acts exactly at the points where the DNA has been damaged. When a break occurs in the DNA, especially within the ribosomal DNA, which is very important for the cell, the presence of alpha-synuclein increases in these places, quickly helping in the repair.

However, when this repair function is performed excessively or uncontrolled, as in melanoma, it allows cells that should die (because they are damaged) to continue living and multiply, leading to the development of cancer.

In addition, when scientists "turned off" the gene that produces alpha-synuclein in melanoma cells, they observed that:

1. The DNA damage increased.

   
   

2. The cells took much longer to repair these breaks.

   
   

3. There was a reduction in the ability of the cells to multiply, migrate and invade new tissues, typical characteristics of cancer.

This behavior shows that alpha-synuclein has a protective role for DNA, but that, in the wrong context (as in melanoma), this protection turns into a dangerous advantage for cancer.

Interestingly, in neurons affected by Parkinson’s, the problem with alpha-synuclein is different. Instead of helping the neuron stay healthy, excess alpha-synuclein causes the protein to leave the nucleus and clump together in the cytoplasm (the part outside the nucleus). These clumps form what are called Lewy bodies, which are toxic to neurons and lead to their death.

In other words, in melanoma, alpha-synuclein remains in the nucleus and protects the DNA so much that it helps the cancer grow. In Parkinson’s, alpha-synuclein leaves the nucleus, forms toxic deposits, and kills brain cells.

This contrast highlights how the same protein can have such opposite effects depending on the cell type and context.

These discoveries open up new possibilities for treatments for both melanoma and Parkinson's:

• In melanoma, the idea would be to develop drugs that block or reduce the function of alpha-synuclein, preventing uncontrolled DNA repair and, consequently, cancer growth.

• In Parkinson's, the strategy could be to replace or support the DNA repair function that alpha-synuclein should perform, perhaps by stimulating other proteins, such as 53BP1, that also help repair DNA breaks.

According to the scientists, understanding alpha-synuclein better could give us tools to treat or even prevent these two diseases that, until recently, seemed completely different.

READ MORE:

Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma

Moriah R Arnold, Gabriel M Cohn, Kezia Catharina Oxe, Somarr N Elliott, Cynthia Moore, Allison May Zhou, Peter V Laraia, Sahar Shekoohi, Dillon Brownell, Rosalie C Sears, Randall L Woltjer, Charles K Meshul, Stephan N Witt, Dorthe H Larsen, Vivek K Unni 

Science Advances. 2025 Apr 11;11 (15): eadq2519

DOI: 10.1126/sciadv.adq2519

Abstract:

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.