Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes

• Published in: Nature neuroscience Vol. 22; no. 7; pp. 1099 - 1109
• Main Authors: Shahmoradian, Sarah H., Lewis, Amanda J., Genoud, Christel, Hench, Jürgen, Moors, Tim E., Navarro, Paula P., Castaño-Díez, Daniel, Schweighauser, Gabriel, Graff-Meyer, Alexandra, Goldie, Kenneth N., Sütterlin, Rosmarie, Huisman, Evelien, Ingrassia, Angela, Gier, Yvonne de, Rozemuller, Annemieke J. M., Wang, Jing, Paepe, Anne De, Erny, Johannes, Staempfli, Andreas, Hoernschemeyer, Joerg, Großerüschkamp, Frederik, Niedieker, Daniel, El-Mashtoly, Samir F., Quadri, Marialuisa, Van IJcken, Wilfred F. J., Bonifati, Vincenzo, Gerwert, Klaus, Bohrmann, Bernd, Frank, Stephan, Britschgi, Markus, Stahlberg, Henning, Van de Berg, Wilma D. J., Lauer, Matthias E.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-07-2019; Nature Publishing Group
• Subjects: 13; 13/1; 14/28; 14/63; 631/535/1258; 64; 692/699/375/1718; Age; alpha-Synuclein - analysis; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Animal Genetics and Genomics; Autopsy; Axons; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Causes of; Coherent scattering; Depletion; Development and progression; Electron microscopy; Etiology; Filaments; Fourier transforms; Hippocampus - chemistry; Hippocampus - ultrastructure; Humans; Image resolution; Imaging, Three-Dimensional; Inclusions; Infrared imaging; Intracellular Membranes - ultrastructure; Lewy bodies; Lewy Bodies - chemistry; Lewy Bodies - ultrastructure; Lewy Body Disease - metabolism; Lewy Body Disease - pathology; Lipid membranes; Lipids; Medical imaging; Membrane Lipids - analysis; Membranes; Mesencephalon - chemistry; Mesencephalon - ultrastructure; Microscopy; Microscopy, Confocal; Microscopy, Electron - methods; Microscopy, Fluorescence; Movement disorders; Neurobiology; Neurodegenerative diseases; Neuroimaging; Neurological diseases; Neurosciences; Organelles; Organelles - ultrastructure; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathogenesis; Pathology; Physiological aspects; Proteins; Raman spectra; Stimulated emission; Substantia Nigra - chemistry; Substantia Nigra - ultrastructure; Synuclein; Whole Exome Sequencing; Netherlands
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-019-0423-2

Parkinson’s disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites: neuronal inclusions immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is crucial to understanding pathogenesis of this disease. Using correlative light and electron microscopy and tomography on postmortem human brain tissue from Parkinson’s disease brain donors, we identified α-synuclein immunopositive Lewy pathology and show a crowded environment of membranes therein, including vesicular structures and dysmorphic organelles. Filaments interspersed between the membranes and organelles were identifiable in many but not all α-synuclein inclusions. Crowding of organellar components was confirmed by stimulated emission depletion (STED)-based super-resolution microscopy, and high lipid content within α-synuclein immunopositive inclusions was corroborated by confocal imaging, Fourier-transform coherent anti-Stokes Raman scattering infrared imaging and lipidomics. Applying such correlative high-resolution imaging and biophysical approaches, we discovered an aggregated protein–lipid compartmentalization not previously described in the Parkinsons’ disease brain.
Using three-dimensional correlative light and electron microscopy of Lewy bodies and Lewy neurites in postmortem brains of Parkinson’s disease patients, researchers show that the major constituents are membranes rather than proteinaceous filaments.