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bioRxiv · 10.1101/2024.07.25.605088

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

Lewis, A.·van den Heuvel, L.·Di Fabrizio, M.·Burger, D.·Huisman, E.·Bol, J. G.·van de Berg, W. D. J.·Stahlberg, H.
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Abstract

Lewy bodies, the defining pathological feature of Parkinsons disease, are intraneuronal inclusions enriched in aggregated alpha-synuclein (Syn). We used correlative light and electron microscopy to selectively investigate phosphorylated Syn (SynpS129)-positive inclusions in the substantia nigra of end-stage postmortem Parkinsons disease brain. Here we show that somatic SynpS129 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 SynpS129 pathology and demonstrate the structural complexity and heterogeneity of Lewy pathology in human Parkinsons disease brain.

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Lewis, A., van den Heuvel, L., Di Fabrizio, M., Burger, D., Huisman, E., Bol, J. G., van de Berg, W. D. J., Stahlberg, H.. 2024-07-25. Ultrastructural diversity of alpha-Synuclein pathology in the post-mortem brain of Parkinson patients: implications for Lewy Body formation. https://doi.org/10.1101/2024.07.25.605088

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