Schwann cell-associated early α-synuclein aggregation in skin biopsies of multiple system atrophy patients
Schwann cell-associated early α-synuclein aggregation in skin biopsies of multiple system atrophy patients
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Original abstract
Abstract Background Parkinson’s disease and multiple system atrophy are synucleinopathies characterized by the presence of cytoplasmic inclusion bodies enriched of α-synuclein within patients’ brain. While Parkinson’s disease inclusions are found within neurons, multiple system atrophy is mostly considered a glial pathology, as inclusions are found within oligodendrocytes. Due to overlapping clinical manifestations, discriminating synucleinopathies in living patients remains an unmet diagnostic need, often leading to misdiagnosis and inadequate clinical management, especially in the early stages. Emerging evidence revealed peripheral α-synuclein aggregation within autonomic synapses in Parkinson’s disease patients, and we have recently shown that the increase of such early aggregated species could predict the worsening of cognitive functions. Methods We investigated the presence and spatial distribution of α-synuclein early aggregated species in skin biopsies obtained from 31 patients affected by multiple system atrophy (16 parkinsonian, 15 cerebellar), 27 Parkinson’s disease patients, and 24 healthy controls, aiming to identify pathology-specific signatures by proximity ligation assay Results We revealed a significant increase in peripheral α-synuclein aggregation within the autonomic synapses of multiple system atrophy patients compared to controls, a feature shared with Parkinson’s disease patients. Importantly, glial specific pathology was identified within the Schwann cells associated to both autonomic fibers and cutaneous nerves. Both the prevalence and the quantitative evaluation of glial α-synuclein aggregates were significantly increased in multiple system atrophy compared to Parkinson’s disease, revealing differential peripheral manifestastions between pathologies. Conclusions Although suboptimal discriminating power in identifying multiple system atrophy versus Parkinson’s disease (specificity = 85%, sensitivity = 62.1%, AUC = 0.739), these findings may still retain clinical relevance within multiparametric diagnostic models, integrating complementary biomarkers and clinical features. Furthermore, we highlight previously unexplored pathological aspects of synucleinopathies, providing evidence for α-synuclein aggregation within peripheral Schwann cells, and further supporting the skin as a suitable site to capture early pathological differences and systemic involvement.