A new study has uncovered a mechanistic link between Parkinson’s and melanoma. While it has been known for about five decades now that patients with Parkinson’s disease have a higher likelihood of developing melanoma than the general population, the exact reasons for this were unknown.
Now, thanks to a study funded by the National Institutes of Health Intramural Research Program, scientists have discovered that α-synuclein, a protein involved in the formation of amyloid deposits in the brain characteristic of Parkinson’s disease and other neurodegenerative disorders, is also implicated in melanoma. It is thought that the amyloid plaques destroy dopamine-producing neurons in the brain, causing symptoms such as tremor, slow movements and dementia.
The scientists found that the amyloid-forming protein is expressed at higher levels in melanoma cells than in normal healthy skin. Additionally, higher levels of α-synuclein in melanocytes — the skin cells that produce melanin and give rise to melanoma — are correlated with reduced melanin production. Melanin is a pigment that protects the skin from damage caused by ultraviolet rays from the sun.
Excessive levels of α-synuclein are implicated in Parkinson’s disease, and the protein is a major component of Lewy bodies, which are clumps of protein that build up in the brain of patients with the disease, causing issues with memory, movement and other daily skills.
The researchers presented their results at the spring meeting of the American Chemical Society (ACS), which is being held online April 5 to 30.
“Several studies have shown that melanoma occurs two to six times more frequently in the Parkinson’s population than the healthy population,” said Dexter Dean, PhD, a postdoctoral fellow at the National Heart, Lung and Blood Institute (NHLBI) who presented the work at the meeting, in a news release from ACS. “What’s more, the protein involved in Parkinson’s disease, α-synuclein, is elevated in melanoma cells.”
In addition to α-synuclein, another amyloid-forming protein called premelanosomal protein (Pmel) has also been implicated in melanoma. Pmel forms amyloid fibrils that function as scaffolds to store melanin in melanosomes — the organelle where melanin is produced, stored and transported — in healthy melanocytes.
Dean’s postdoctoral advisor at NHLBI, Jennifer Lee, PhD, had previously studied Pmel and suggested a potential link between α-synuclein and Pmel.
“Because both α-synuclein and Pmel are expressed in melanoma cells, we wondered if these two amyloid proteins could interact, and whether this interaction could be relevant to the correlation between Parkinson’s disease and melanoma,” Lee said.
The researchers showed that both α-synuclein and Pmel proteins were present in the melanosomes of human melanoma cells. To examine whether the two proteins could interact, Dean added preformed α-synuclein amyloid to a test tube containing the amyloid-forming region of Pmel (known as the repeat, or RPT, domain) and found that the α-synuclein fibrils stimulated the aggregation of Pmel to form a twisted fibril structure that the protein does not typically adopt on its own.
Furthermore, since α-synuclein can also be found in its soluble, or non-amyloid, form, in melanoma cells, the researchers performed additional in vitro experiments in which they added soluble α-synuclein to the Pmel RPT domain. It was found that soluble α-synuclein actually inhibited Pmel self-aggregation and led to formation of amyloid in a concentration-dependent manner.
“We now have preliminary data that suggest an amyloid from one protein can ‘seed’ or template amyloid from another, and in the soluble form, α-synuclein prevents Pmel aggregation,” Lee said. “Therefore, we think that both forms of α-synuclein could diminish melanin biosynthesis — the amyloid form by causing Pmel to form an unusual, twisted structure, and the soluble form by stopping Pmel from aggregating like it should.”
Based on this preliminary data, the researchers say that loss of skin pigmentation could contribute to the increased melanoma risk in Parkinson’s disease patients.
Targeting α-synuclein has been an important area of research in Parkinson’s disease. For example, gene therapy approaches are being investigated to downregulate α-synuclein synthesis in the brain. This could have important implications for managing and treating Parkinson’s, as well as potentially targeting melanoma. Furthermore, targeting Pmel and its interaction with α-synuclein in melanoma cells, or healthy melanocytes before the development of melanoma, could be a potential therapeutic or preventative approach against melanoma in Parkinson’s patients.