Stochastic Optical Reconstruction Microscopy Imaging of Multiple System Atrophy Inclusions Suggests Stepwise α‐Synuclein Aggregation

Abstract

BackgroundThe architecture and composition of glial (GCI) and neuronal (NCI) α‐synuclein inclusions observed in multiple system atrophy (MSA) remain to be precisely defined to better understand the disease.MethodsHere, we used stochastic optical reconstruction microscopy (STORM) to characterize the nanoscale organization of glial (GCI) and neuronal (NCI) α‐synuclein inclusions in cryopreserved brain sections from MSA patients.ResultsSTORM revealed a dense cross‐linked internal structure of α‐synuclein in all GCI and NCI. The internal architecture of hyperphosphorylated α‐synuclein (p‐αSyn) inclusions was similar in glial and neuronal cells, suggesting a common aggregation mechanism. A similar sequence of p‐αSyn stepwise intracellular aggregation was defined in oligodendrocytes and neurons, starting from the perinuclear area and growing inside the cells. Consistent with this hypothesis, we found a higher mitochondrial density in GCI and NCI compared to oligodendrocytes and neurons from unaffected donors (P < 0.01), suggesting an active recruitment of the organelles during the aggregation process.ConclusionsThese first STORM images of GCI and NCI suggest stepwise α‐synuclein aggregation in MSA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.