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

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 MSA-P and 17 MSA-C), 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 5 different medical centres. P-syn aggregates in skin sections were stained by immunofluorescence, followed by analyses with confocal microscopy (IFC) and immuno-electron microscopy (IEM). 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 analyzing 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 IEM confirmed that SCCi were only found in cases with MSA and thus absent in those with PD/DLB. In conclusions our findings demonstrate that 1) fibrillar p-syn in RSCs is a pathological hallmark of MSA and may be used as a specific and sensitive disease biomarker; 2) in Lewy body synucleinopathies (PD/DLB) only neurons contain p-syn deposits; 3) the cell-specific deposition of p-syn in the skin thus mirrors that of the brain in many aspects and suggests that also non-myelinated glial cells are involved in the MSA pathogenesis.