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

Abstract

Lewy bodies, the major pathological hallmark of Parkinson’s disease, are intraneuronal inclusions rich in aggregated alpha-synuclein (aSyn). To understand the cellular mechanisms behind the formation of Lewy bodies and the aggregation of aSyn, we used correlative light and electron microscopy and detailed ultrastructural analysis of postmortem brain tissue samples of Parkinson patients. We found that somal aSyn inclusions in dopaminergic neurons were exclusively fibrillar, while membranous-type inclusions were located outside the cell soma and likely compact neuritic aggregates. These neuritic inclusions displayed phenotypic heterogeneity, ranging from predominantly membranous to mixed membranous/fibrillar ultrastructures. Our data suggest that membranous and fibrillar aSyn inclusions form via distinct mechanisms, with membranous neuritic inclusions providing the environment for the initial nucleation of aSyn fibrils, which could then spread via a prion-like mechanism to form somal fibrillar Lewy bodies. This study provides important insight into Lewy body formation and highlights the importance of aSyn and membrane interactions for future therapeutic intervention.