Researchers at the National Heart, Lung, and Blood Institute have discovered a connection between the problematic molecules that appear in cases of melanoma and Parkinson's disease, providing a clue that could one day inform new treatments for both diseases.
Jennifer Lee, a senior investigator who runs an independent lab at the NHLBI, a division of the National Institutes of Health, and Dexter Dean, a postdoctoral fellow who has worked with Lee since 2018, are presenting their preliminary findings at the spring meeting of the American Chemical Society on April 7.
Scientists think that one cause of Parkinson's disease is the buildup of a protein called alpha-synuclein, which is commonly found in brain tissue and other regions of the body. In Parkinson's, an abundance of alpha-synuclein leads to cell death, but, as is the case with any cancer, melanoma is characterized by the opposite phenomenon — skin cells multiplying out of control.
Yet researchers are certain that the two diseases have a connection: Patients with Parkinson's disease are two to six times as likely to develop melanoma, and, in turn, melanoma patients have around a fourfold greater likelihood of developing Parkinson's. Meanwhile, it appears that people with Parkinson's have a reduced chance of developing other types of cancer. But so far, scientists have been unable to pin down what, exactly, is behind this unusual relationship.
"This [link] was first suggested nearly 50 years ago, and we still don't have really a concrete answer as to why, molecularly, these two diseases are connected," Dean told The Academic Times.
In previous studies, the NHLBI team established that alpha-synuclein proteins were more prevalent in melanoma cells compared with healthy skin cells. A higher concentration of alpha-synuclein was also found to reduce the production of melanin, a pigment that protects the skin from harmful sun radiation that can sometimes lead to melanoma.
Next, the NHLBI researchers questioned how alpha-synuclein interacted with other proteins found in melanin — in particular, one with similar clumping properties called Pmel. Unlike other proteins that have the potential to tangle and lead to the kind of cell breakdown seen in Parkinson's, Pmel may play a positive role in the body by helping support and regulate melanin production. But the researchers posited that alpha-synuclein may have the ability to interrupt or alter Pmel's function in melanin cells.
They placed alpha-synuclein proteins into a test tube with a relevant portion of the Pmel protein and, with the help of a microscope, observed how they interacted. During the experiments, Lee and Dean found that, when exposed to alpha-synuclein, Pmel began clumping and twisting into an unusual formation that it is not able to assemble on its own.
Additionally, the researchers allowed a soluble version of alpha-synuclein to interact with a portion of Pmel, which caused Pmel to lose its ability to congeal and connect. The experiments showed that alpha-synuclein could shape and control the behavior of Pmel proteins, marking a new breakthrough in the study of amyloids, the proteins that bind and clump to cause a number of diseases in the body.
The researchers explained that the proteins' relationship should be observed with caution, since their interactions do not necessarily relate to the mechanisms that determine whether a person will develop Parkinson's or melanoma.
"We can look at the interactions of these two proteins in vitro. But to try to bridge the gap from something that's a biochemical interaction — to kind of translate that and say this might be the explanation in humans — it's a far reach," Lee said. "So I think that's the challenge. We try to stay grounded."
In Parkinson's, tangled bundles of alpha-synuclein grow into Lewy bodies that can cause neurons to die off. The disease specifically damages a region of the brain responsible for dopamine production, resulting in physical symptoms such as body tremors and stiffness, as well as psychiatric issues, including dementia and anxiety.
Around 60,000 Americans are diagnosed with Parkinson's each year, and roughly 10 million people worldwide live with the disease, according to the Parkinson's Foundation. Melanoma, the most dangerous form of skin cancer, presents a considerable health risk, too, killing roughly 9,000 people in the United States each year.
Lee and Dean said they combined their expertise to uncover a hidden relationship between two seemingly distant diseases. This resourceful thinking, the researchers hope, may one day provide insight into the underlying conditions that lead to both diseases.
"It's kind of interesting thinking about a brain disease versus something that's happening on our skin. But these cells are actually related," Lee said. "So we're sort of teasing out the molecular interactions that are responsible for these two essential players."
The presentation, "An amyloid link between Parkinson's disease and melanoma," was given on April 7 by Jennifer Lee and Dexter Dean, the National Heart, Lung, and Blood Institute, a division of the National Institutes of Health.