The Presence of Alpha-Synuclein in Skin from Melanoma and Patients with Parkinson's Disease

Abstract

Background: The misfolding and prion-like propagation of the protein α-synuclein (α-syn) is the leading molecular signature in Parkinson's disease (PD). There is a significant coincidence of PD and melanoma that may suggest a shared pathophysiology. This study compared the presence of α-syn in neural crest-derived tissues, such as nevi, melanoma, skin tags, and skin biopsies from patients with PD and healthy controls.

Methods: Biopsies from participants with PD were obtained from patients from a tertiary referral center for dermatology and neurology in Mexico and a private dermatopathology center in Florida between January 2015 and March 2016. Biopsies from 7 patients with melanoma, 15 with nevi, 9 with skin tags, 8 with PD, and 9 skin biopsies from healthy volunteers were analyzed for immunohistochemical determination of α-syn and tyrosinase. All analyses were performed by pathologists who were blinded with respect to the clinical diagnosis.

Results: In healthy controls, positive α-syn status was restricted to scattered cells in the basal layer of the epidermis and accounted for 1 ± 0.8% of the analyzed area. In patients with PD, there was increased staining for α-syn PD (3.3 ± 2.3%), with a higher percentage of positive cells in nevi (7.7 ± 5.5%) and melanoma (13.6 ± 3.5%). There was no increased staining in skin tags compared with healthy controls.

Conclusion: Patients with PD and melanoma have increased staining for α-syn in their skin. The authors propose that neurons and melanocytes, both derived from neuroectodermal cells, may share protein synthesis and regulation pathways that become dysfunctional in PD and melanoma.

Keywords: Parkinson disease; melanoma; proteinopathies; α‐synuclein.

Figures

Figure 1

Alpha‐synuclein (α‐syn) expression in the epidermis. (Top) Details of skin structure show the epidermis, melanin in the cytoplasm of keratinocytes, tyrosinase‐positive cells (melanocytes) revealed by immunohistochemistry, and dermis. A: Healthy control sample with α‐syn immunopositivity in scattered cells of the basal layer of the epidermis. B: Parkinson disease sample with multiple α‐syn–immunopositive cells in the basal layer, intercellular spaces, and cytoplasm of some keratinocytes. C: In a compound nevus, α‐syn–positive cells in the dermis and epidermis reach several rows of keratinocytes. D: In melanoma, intense immunopositivity is observed along all epidermis strata (amino‐ethylcarbazole staining; scale bar = 10 μm).

Figure 2

Different patterns of melanin and alpha‐synuclein (α‐syn) expression in the epidermis. A: A skin tag has abundant melanin in the basal layer of the epidermis but scarce α‐syn immunopositivity (scale bar = 30 μm). B: A sample from a patient with Parkinson's disease has abundant melanin and α‐syn in basal and spinous strata of the epidermis. C: In melanoma, epithelioid melanocytes are observed at the junction and in the papillary dermis with intense α‐syn immunopositivity and some pigmented cells (scale bar = 10 μm).

Figure 3

Immunofluorescence patterns of alpha‐synuclein (α‐syn) and tyrosinase expression in melanoma. A: Confocal microscopy reveals α‐syn (Alexa Fluor 488; green) and tyrosinase (cyanine 5; blue) antibodies. Cell nuclei were stained with SYTOX (Thermo Fisher Scientific; scale bar = 10 μm). B: Panoramic image of a melanoma section. C: Immunopositivity for α‐syn is localized in cytoplasm, nuclei, and intercellular spaces along the epidermis. D: Tyrosinase immunopositivity is restricted to the cytoplasm, mostly in epithelioid melanocytes of the basal layer; this merged image reveals only limited colocalization of α‐syn and tyrosinase immunopositivity in basal cells and some keratinocytes.

Figure 4

Skin immunofluorescence is observed in nevus (A–C), Parkinson's disease (D–F), and healthy controls (G–I). Arrows in (A) and (D) indicate the spreading of α‐syn along intercellular spaces and nuclei; and arrows in B and E indicate the cytoplasm localization of tyrosinase. G and H: Scattered immunopositive cells are observed in the basal layer of epidermis from healthy controls. Merged images in (C, F, and I) show the limited colocalization of α‐syn and tyrosinase immunopositivity (confocal microscopy; α‐syn [Alexa Fluor 488] and tyrosinase [Cy5] antibodies). Cell nuclei were stained with SYTOX. Scale bar = 10 μm.

Figure 5

Immunopositivity for alpha‐synuclein (α‐syn) is expressed as the percentage of immunopositive pixels/total area. Immunoreactivity for α‐syn in the Parkison's disease (PD), nevi, and melanoma groups was significantly different from that in healthy controls (HC) (*P < 0.0125, ***P < 0.001). Bars represent medians and interquartile ranges. Kruskal‐Wallis analyses were followed by Mann‐Whitney U tests.