Ultrastructural diversity and subcellular organization of nigral Lewy pathology in Parkinson’s disease

Lewy bodies, the defining pathological feature of Parkinson’s disease, are intraneuronal inclusions enriched in aggregated alpha-synuclein (αSyn). We used correlative light and electron microscopy to selectively investigate phosphorylated αSyn (αSyn pS129 )-positive inclusions in the substantia nigra of end-stage postmortem Parkinson’s disease brain. Here we show that somatic αSyn pS129 inclusions in nigral dopaminergic neurons are consistently fibrillar, whereas the membranous-type inclusions are restricted to neuritic processes. These neuritic inclusions displayed marked ultrastructural heterogeneity, ranging from predominantly membranous to mixed membranous-fibrillar forms. The selective targeting of defined inclusions enabled detailed structural characterization of Lewy pathology, rather than quantitative or disease-stage comparisons. Our findings highlight clear ultrastructural differences between somatic and neuritic αSyn pS129 pathology and demonstrate the structural complexity and heterogeneity of Lewy pathology in human Parkinson’s disease brain.