An amyloid link between Parkinson’s disease and melanoma

At first glance, Parkinson’s disease – a neurodegenerative disorder – and melanoma – a type of skin cancer – do not seem to have much in common. However, for nearly 50 years, doctors have realized that patients with Parkinson’s disease develop more melanoma than the general population. Scientists are now reporting a molecular link between the two diseases in the form of protein aggregates, known as amyloids.

The researchers will present their results today at the spring meeting of the American Chemical Society (ACS).

“Several studies have shown that melanoma is two to six times more common in the Parkinson’s population than the healthy population,” said Dexter Dean, Ph.D., a postdoctoral fellow at the National Institute for Heart, Lung and Blood Institute (NHLBI). ), who presents the work during the meeting. “What’s more, the protein involved in Parkinson’s disease, α-synuclein, has been increased in melanoma cells.”

In Parkinson’s disease, α-synuclein forms amyloid deposits that are thought to kill dopamine-producing neurons in the brain, causing symptoms such as tremors, slow movements, and dementia. While intensive research has focused on the effects of α-synuclein in the brain, much less is known about its occurrence or activities in other tissues. However, scientists have evidence that the amyloid-forming protein is more expressed in melanoma cells in healthy skin. Furthermore, higher levels of α-synuclein in melanocytes (the skin cells that give rise to melanoma) correlate with decreased production of pigment, or melanin. Melanin protects the skin from damage by the sun’s ultraviolet rays.

Jennifer Lee, Ph.D., Dean’s postdoctoral advisor at NHLBI, part of the National Institutes of Health, previously studied another amyloid-forming protein called premelanosomal protein (Pmel). “Most people know that amyloids are involved in diseases like Parkinson’s and Alzheimer’s, but it’s less well known that some amyloids, like Pmel, have a beneficial function,” says Lee. In healthy melanocytes, Pmel forms amyloid fibrils that act as scaffolds to store melanin in melanosomes (the organelle where the pigment is produced, stored, and transported). “Because both α-synuclein and Pmel are expressed in melanoma cells, we wondered whether these two amyloid-protein interactions might occur, and whether this interaction might be relevant to the correlation between Parkinson’s disease and melanoma,” says Lee.

To investigate whether α-synuclein and Pmel may interact, the researchers used microscopy and western blotting to show that the two proteins are both present in the melanosomes of human melanoma cells. When Dean added preformed α-synuclein amyloid to a test tube containing the amyloid-forming region of Pmel (known as the repeat, or RPT, domain), the α-synuclein fibrils stimulated Pmel to join together and form a twisted fibril structure. form that the protein normally accepts not alone.

Because α-synuclein in melanoma cells can also be found in its soluble, or non-amyloidic form, the researchers performed other in vitro experiments in which they added soluble α-synuclein to the Pmel RPT domain. In this case, α-synuclein inhibited Pmel’s ability to combine and form amyloid in a concentration-dependent manner. They detected this activity after the first 60 amino acids of α-synuclein.

“We now have preliminary data suggesting that an amyloid from one protein may form ‘amyloid’ from another ‘seed’ or a pattern, and in the soluble form, α-synuclein Pmel aggregation occurs. ‘Lee says. “Therefore, we think that both forms of α-synuclein can reduce melanin biosynthesis – the amyloid form by allowing Pmel to form an unusually twisted structure, and the soluble form by preventing Pmel from accumulating as it should.” Loss of skin pigmentation may contribute to the increased melanoma risk in patients with Parkinson’s disease, the researchers say.

“I think we’re just at the tip of the iceberg to appreciate what α-synuclein can do in melanoma,” says Dean. “In future experiments, I’m really interested in understanding more about what α-synuclein does to promote the spread of melanoma, in addition to this interaction with Pmel.”

More information:
Abstract title: Definition of an amyloid link between Parkinson’s disease and melanoma