Ultrastructural diversity of alpha-Synuclein pathology in the post-mortem brain of Parkinson patients: implications for Lewy Body formation

Lewy bodies, the major pathological hallmark of Parkinsons disease, are intraneuronal inclusions rich in aggregated alpha-synuclein (Syn). To understand the cellular mechanisms behind the formation of Lewy bodies and the aggregation of Syn, we used correlative light and electron microscopy to perform detailed ultrastructural analysis of phosphorylated Syn (SynpS129)-positive inclusions in the substantia nigra of postmortem Parkinsons disease brain. Building on our previous observations highlighting the significance of membranous pathology in Parkinsons disease, we found that somal SynpS129 inclusions in nigral dopaminergic neurons were consistently fibrillar, while the membranous-type inclusions were exclusively located in neuritic processes. The neuritic inclusions displayed phenotypic heterogeneity, ranging from predominantly membranous to mixed membranous/fibrillar ultrastructures. Our observations from human brain suggest that membranous and fibrillar Syn inclusions form via distinct mechanisms, and that the membranous neuritic inclusions may provide an environment conducive to the initial nucleation of Syn fibrils. This study underlines the distinction between membranous and fibrillar SynpS129 inclusions in Parkinsons disease and highlights the ultrastructural complexity of Lewy pathology in human brain.