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

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 analy...

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Vydáno v:	Nature neuroscience Ročník 22; číslo 7; s. 1099 - 1109
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Nature Publishing Group 01.07.2019
Témata:	Age alpha-Synuclein - analysis Alzheimer Disease - metabolism Alzheimer Disease - pathology Autopsy Axons Brain Coherent scattering Correlation Depletion 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 Neurodegenerative diseases Neuroimaging Neurological diseases Organelles Organelles - ultrastructure Parkinson Disease - metabolism Parkinson Disease - pathology Parkinson's disease Pathogenesis Pathology Proteins Raman spectra Stimulated emission Substantia Nigra - chemistry Substantia Nigra - ultrastructure Synuclein Whole Exome Sequencing
ISSN:	1097-6256, 1546-1726, 1546-1726
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1097-6256 1546-1726 1546-1726
DOI:	10.1038/s41593-019-0423-2