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

Shahmoradian SH; Lewis AJ; Genoud C; Hench J; Moors TE; Navarro PP; Castaño-Díez D; Schweighauser G; Graff-Meyer A; Goldie KN; Sütterlin R; Huisman E; Ingrassia A; Gier Y; Rozemuller AJM; Wang J; Paepe A; Erny J; Staempfli A; Hoernschemeyer J; Großerüschkamp F; Niedieker D; El-Mashtoly SF; Quadri M; Van IJcken WFJ; Bonifati V; Gerwert K; Bohrmann B; Frank S; Britschgi M; Stahlberg H; Van de Berg WDJ; Lauer ME

doi:10.1038/s41593-019-0423-2

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Journal article

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

Shahmoradian SH Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland.
Lewis AJ Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland.
Genoud C Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Hench J Division of Neuropathology, Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Moors TE Amsterdam Neuroscience, VU University Medical Center, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy, Amsterdam, The Netherlands.
Navarro PP Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland.
Castaño-Díez D Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland.
Schweighauser G Division of Neuropathology, Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Graff-Meyer A Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Goldie KN Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland.
Sütterlin R Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland.
Huisman E Amsterdam Neuroscience, VU University Medical Center, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy, Amsterdam, The Netherlands.
Ingrassia A Amsterdam Neuroscience, VU University Medical Center, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy, Amsterdam, The Netherlands.
Gier Y Amsterdam Neuroscience, VU University Medical Center, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy, Amsterdam, The Netherlands.
Rozemuller AJM Amsterdam Neuroscience, VU University Medical Center, Department of Pathology, Amsterdam, The Netherlands.
Wang J Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland.
Paepe A Roche Pharma Research and Early Development, Lead Discovery, Roche Innovation Center Basel, Basel, Switzerland.
Erny J Roche Pharma Research and Early Development, Preclinical CMC, Roche Innovation Center Basel, Basel, Switzerland.
Staempfli A Roche Pharma Research and Early Development, Preclinical CMC, Roche Innovation Center Basel, Basel, Switzerland.
Hoernschemeyer J Roche Pharma Research and Early Development, Preclinical CMC, Roche Innovation Center Basel, Basel, Switzerland.
Großerüschkamp F Department of Biophysics, Ruhr University, Bochum, Germany.
Niedieker D Department of Biophysics, Ruhr University, Bochum, Germany.
El-Mashtoly SF Department of Biophysics, Ruhr University, Bochum, Germany.
Quadri M Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Van IJcken WFJ Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands.
Bonifati V Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Gerwert K Department of Biophysics, Ruhr University, Bochum, Germany.
Bohrmann B Roche Pharma Research and Early Development, Neuroscience, Ophthalmology, and Rare Diseases Discovery and Translational Area/Neuroscience Discovery, Roche Innovation Center Basel, Basel, Switzerland.
Frank S Division of Neuropathology, Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Britschgi M Roche Pharma Research and Early Development, Neuroscience, Ophthalmology, and Rare Diseases Discovery and Translational Area/Neuroscience Discovery, Roche Innovation Center Basel, Basel, Switzerland.
Stahlberg H Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Basel, Switzerland. henning.stahlberg@unibas.ch.
Van de Berg WDJ Amsterdam Neuroscience, VU University Medical Center, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy, Amsterdam, The Netherlands. wdj.vandeberg@vumc.nl.
Lauer ME Roche Pharma Research and Early Development, Lead Discovery, Roche Innovation Center Basel, Basel, Switzerland. matthias.lauer@roche.com.

2019-06-26

Published in:

Nature neuroscience. - 2019

English 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.

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