Abstract

Parkinson’s disease (PD) is diagnosed postmortem by alpha-synuclein (aSyn) immunopositive neuronal inclusions, known as Lewy bodies and Lewy neurites. Despite previous analyses by electron microscopy and immunostainings, the small pathogenic building blocks of Lewy pathology in PD remain controversial, mainly due to the lack of high-quality ultrastructural and correlative data on aSyn-labeled aggregates in human brain tissue.
We applied correlative light and electron microscopy (CLEM) and 3D transmission electron tomography on postmortem brain of Parkinson’s patients collected through rapid-autopsy protocols. In addition multi-labeling stimulated emission depletion (STED) microscopy, chemical mapping-imaging, and mass spectrometry-based lipidomics was applied to analyze Lewy pathology.
We discovered abundant membrane fragments, vesicular structures, and mitochondria in alpha-synuclein-labeled Lewy bodies and similarly in Lewy neurites, the majority of which did not show predominant filamentous structures. We could identify a very small fraction of aSyn-immunopositive structures predominantly containing filaments. The lipid content identity and membrane-like profile of Lewy bodies was confirmed by lipidomics and chemical mapping-imaging on adjacent tissue sections. STED revealed co-localization of phosphorylated aSyn and specific markers of organelles such as mitochondria or lysosomes within Lewy pathology.
Our data obtained in well-preserved postmortem human brain demonstrate that Lewy bodies in PD consist of a crowded medley of distorted organelles and fragmented membranes rather than proteinacious clumps. We propose that pathologically modified aSyn plays an active role in the formation of this pathology, including the disruption of lipid membranes and crowding of vesicular structures.

1) Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes Nature Neuroscience (2019), doi: 10.1038/s41593-019-0423-2