Revisiting the alpha-synuclein paradox in melanoma-Parkinson’s disease connection: more than a tale of two cell fates

Abstract Since the first report in 1972, several studies have documented an association between Parkinson’s disease (PD) and melanoma. Up to 20-fold increased risk of melanoma was reported in PD patients, while a personal/family history of melanoma was linked to a 1.85-fold PD risk. Neurons and melanocytes, which both derive from the neuroectodermal crest, share biological pathways that may be dysregulated in both diseases. In particular, accumulation of the alpha-synuclein (α-syn, SNCA) protein, a pathological hallmark of PD, is also observed in melanoma. Indeed, dysregulated α-syn proteostasis is known to disrupt several biological pathways which can co-incidentally, albeit paradoxically contribute to both neurodegeneration and hyper-proliferative cell growth. These include abnormalities in dopamine (DA), melanin, and iron metabolism, oxidative stress, DNA damage/repair response, inflammation, as well as alterations in mitochondrial function, and cell-clearing machinery. Although α-syn depletion was shown to attenuate melanoma cell proliferation and neurodegeneration, it remains unclear whether α-syn accumulation is a mere culprit of disease, if it represents a common outcome from shared upstream mechanisms, or, finally, a compensatory response to cellular stress. In an effort to elucidate how α-syn bridges melanomagenesis and the neurodegenerative events of PD, this review discusses specific cellular and molecular pathways related to α-syn proteostasis, including environmental factors implicated in melanocytic transformation, such as UV radiation. Addressing open questions and establishing novel experimental models remain essential for developing effective therapeutic approaches to target melanoma and PD without overlooking their comorbidity.