Nuclear Alpha-Synuclein in Parkinson's Disease and the Malignant Transformation in Melanoma

Background: Alpha-synuclein (ASyn), a marker of Parkinson's disease (PD) and other neurodegenerative processes, plays pivotal roles in neuronal nuclei and synapses. ASyn and its phosphorylated form at Serine 129 (p-ASyn) are involved in DNA protection and repair, processes altered in aging, neurodegeneration, and cancer. Objective: To analyze the localization of p-ASyn in skin biopsies of PD patients and melanoma. Methods: Biopsies from 26 PD patients, 20 melanoma patients, and 31 control subjects were probed and analyzed with a p-ASyn antibody by immunohistochemistry and immunofluorescence. Nuclear positivity was quantified by image analysis. Results: Peripheral nerve endings from healthy subjects show little p-ASyn immunopositivity but notable axonal presence in PD. Control subjects show immunopositivity to p-ASyn along all epidermic strata and scarce presence in their cytoplasm. In contrast, its nuclear presence in PD is weaker, with a higher cytoplasmic and intercellular presence. Nuclear p-ASyn in melanoma varied from similar to control skin in early stage melanoma to a higher rate of empty nuclei in the intermediate stage and total absence of nuclear p-ASyn in severe cases. Interpretation: These findings support the nuclear localization of p-ASyn in skin cells and show that its presence decreases PD and almost disappears in the malignant transformation of melanocytes, redistributing to the cytoplasm and intercellular spaces. This confirms the association between PD and melanoma, providing crucial insights into the role of p-ASyn in both diseases. Trial Registration: ClinicalTrials.gov identifier: NCT01380899.