Phosphorylated α-synuclein in skin Schwann cells: a new biomarker for multiple system atrophy

• Published in: Brain (London, England : 1878) Vol. 146; no. 3; pp. 1065 - 1074
• Main Authors: Donadio, Vincenzo, Incensi, Alex, Rizzo, Giovanni, Westermark, Gunilla T, Devigili, Grazia, De Micco, Rosa, Tessitore, Alessandro, Nyholm, Dag, Parisini, Sara, Nyman, Dag, Tedeschi, Gioacchino, Eleopra, Roberto, Ingelsson, Martin, Liguori, Rocco
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.03.2023
• Subjects: alpha-Synuclein - metabolism; Alzheimer Disease; biomarker; Biomarkers; Cross-Sectional Studies; fibrillar alpha-synuclein; Humans; Lewy Body Disease - metabolism; multiple system atrophy; Multiple System Atrophy - pathology; Parkinson Disease - pathology; Schwann Cells; skin biopsy; skin non-myelinating Schwann cell; skin non-myelinating Schwann cell; fibrillar α-synuclein; multiple system atrophy; biomarker; skin biopsy
• DOI: 10.1093/brain/awac124
• ISSN: 0006-8950; 1460-2156

Abstract Multiple system atrophy (MSA) is characterized by accumulation of phosphorylated α-synuclein (p-syn) as glial cytoplasmic inclusions in the brain and a specific biomarker for this disorder is urgently needed. We aimed at investigating if p-syn can also be detected in skin Remak non-myelinating Schwann cells (RSCs) as Schwann cell cytoplasmic inclusions (SCCi) and may represent a reliable clinical biomarker for MSA. This cross-sectional diagnostic study evaluated skin p-syn in 96 patients: 46 with probable MSA (29 with parkinsonism type MSA and 17 with cerebellar type MSA), 34 with Parkinson's disease (PD) and 16 with dementia with Lewy bodies (DLB). We also included 50 healthy control subjects. Patients were recruited from five different medical centres. P-syn aggregates in skin sections were stained by immunofluorescence, followed by analyses with confocal microscopy and immuno-electron microscopy. All analyses were performed in a blinded fashion. Overall, p-syn aggregates were found in 78% of MSA patients and 100% of patients with PD/DLB, whereas they could not be detected in controls. As for neuronal aggregates 78% of MSA patients were positive for p-syn in somatic neurons, whereas all PD/DLB patients were positive in autonomic neurons. When analysing the presence of p-syn in RSCs, 74% of MSA patients were positive, whereas no such SCCi could be observed in PD/DLB patients. Analyses by immuno-electron microscopy confirmed that SCCi were only found in cases with MSA and thus absent in those with PD/DLB. In conclusion, our findings demonstrate that (i) fibrillar p-syn in RSCs is a pathological hallmark of MSA and may be used as a specific and sensitive disease biomarker; (ii) in Lewy body synucleinopathies (PD/DLB) only neurons contain p-syn deposits; and (iii) the cell-specific deposition of p-syn in the skin thus mirrors that of the brain in many aspects and suggests that non-myelinated glial cells are also involved in the MSA pathogenesis. Donadio et al. report that fibrillar phosphorylated α-synuclein accumulation in skin non-myelinating Schwann cells could be a specific and sensitive biomarker for MSA. The findings provide a novel cell-based model in which to study MSA pathogenetic mechanisms underlying the accumulation of glial cytoplasmic inclusions.