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Lewy pathology in Parkinson’s disease consists of a crowded organellar membranous medley

Sarah H. Shahmoradian, Christel Genoud, Alexandra Graff-Meyer, Jürgen Hench, Tim Moors, Gabriel Schweighauser, Jing Wang, Kenneth N. Goldie, Rosmarie Sütterlin, Daniel Castaño-Díez, Paula Pérez-Navarro, Evelien Huisman, Sabine Ipsen, Angela Ingrassia, Yvonne de Gier, Annemieke J.M. Rozemuller, Anne De Paepe, Johannes Erny, Andreas Staempfli, Joerg Hoernschemeyer, Frederik Großerüschkamp, Daniel Niedieker, Samir F. El-Mashtoly, Marialuisa Quadri, Wilfred F.J. van IJcken, Vincenzo Bonifati, Klaus Gerwert, Bernd Bohrmann, Stephan Frank, Markus Britschgi, Henning Stahlberg, Wilma D. J. van de Berg, Matthias E. Lauer
doi: https://doi.org/10.1101/137976
Sarah H. Shahmoradian
Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Switzerland
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Christel Genoud
Friedrich Miescher Institute for Biomedical Research, Switzerland
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Alexandra Graff-Meyer
Friedrich Miescher Institute for Biomedical Research, Switzerland
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Jürgen Hench
Division of Neuropathology, Institute of Pathology, University Hospital Basel, Switzerland.
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Tim Moors
Department of Anatomy and Neurosciences, section Clinical Neuroanatomy, AO | 2M, Amsterdam Neuroscience, VU University Medical Center, Netherlands
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Gabriel Schweighauser
Division of Neuropathology, Institute of Pathology, University Hospital Basel, Switzerland.
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Jing Wang
Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Switzerland
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Kenneth N. Goldie
Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Switzerland
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Rosmarie Sütterlin
Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Switzerland
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Daniel Castaño-Díez
Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Switzerland
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Paula Pérez-Navarro
Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Switzerland
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Evelien Huisman
Department of Anatomy and Neurosciences, section Clinical Neuroanatomy, AO | 2M, Amsterdam Neuroscience, VU University Medical Center, Netherlands
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Sabine Ipsen
Division of Neuropathology, Institute of Pathology, University Hospital Basel, Switzerland.
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Angela Ingrassia
Department of Anatomy and Neurosciences, section Clinical Neuroanatomy, AO | 2M, Amsterdam Neuroscience, VU University Medical Center, Netherlands
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Yvonne de Gier
Department of Anatomy and Neurosciences, section Clinical Neuroanatomy, AO | 2M, Amsterdam Neuroscience, VU University Medical Center, Netherlands
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Annemieke J.M. Rozemuller
Department of Pathology, Amsterdam Neuroscience, VU University Medical Center, Netherlands
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Anne De Paepe
Roche Pharma Research and Early Development, Chemical Biology, Roche Innovation Center Basel, Basel, Switzerland
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Johannes Erny
Roche Pharma Research and Early Development, Preclinical CMC, Roche Innovation Center Basel, Basel, Switzerland
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Andreas Staempfli
Roche Pharma Research and Early Development, Preclinical CMC, Roche Innovation Center Basel, Basel, Switzerland
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Joerg Hoernschemeyer
Roche Pharma Research and Early Development, Preclinical CMC, Roche Innovation Center Basel, Basel, Switzerland
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Frederik Großerüschkamp
Department of Biophysics, Ruhr University Bochum, Germany
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Daniel Niedieker
Department of Biophysics, Ruhr University Bochum, Germany
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Samir F. El-Mashtoly
Department of Biophysics, Ruhr University Bochum, Germany
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Marialuisa Quadri
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands
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Wilfred F.J. van IJcken
Center for Biomics, Erasmus Medical Center, Rotterdam, Netherlands
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Vincenzo Bonifati
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands
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Klaus Gerwert
Department of Biophysics, Ruhr University Bochum, Germany
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Bernd Bohrmann
Roche Pharma Research and Early Development, NORD DTA/Neuroscience Discovery, Roche Innovation Center Basel, Basel, Switzerland
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Stephan Frank
Division of Neuropathology, Institute of Pathology, University Hospital Basel, Switzerland.
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Markus Britschgi
Roche Pharma Research and Early Development, NORD DTA/Neuroscience Discovery, Roche Innovation Center Basel, Basel, Switzerland
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Henning Stahlberg
Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Switzerland
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Wilma D. J. van de Berg
Department of Anatomy and Neurosciences, section Clinical Neuroanatomy, AO | 2M, Amsterdam Neuroscience, VU University Medical Center, Netherlands
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Matthias E. Lauer
Roche Pharma Research and Early Development, Chemical Biology, Roche Innovation Center Basel, Basel, Switzerland
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Summary

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, which are neuronal inclusions that are immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is key to understanding pathogenesis and progression of the disease. Using correlative light and electron microscopy on postmortem brain tissue of Parkinson’s patients, we discovered a crowded membranous medley of vesicular structures, dysmorphic mitochondria and disrupted cytoskeletal elements in Lewy bodies and Lewy neurites, rather than the widely expected proteinacious filaments. The collapse and crowding of central organellar components was confirmed by stimulated emission-depletion microscopy, and chemical and optical imaging. A high lipid content was confirmed by lipidomics. The findings indicate ill-defined subcellular protein-lipid compartmentalization and point toward impaired organellar trafficking as a key driver of pathogenesis in Parkinson’s disease.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 16, 2017.
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Lewy pathology in Parkinson’s disease consists of a crowded organellar membranous medley
Sarah H. Shahmoradian, Christel Genoud, Alexandra Graff-Meyer, Jürgen Hench, Tim Moors, Gabriel Schweighauser, Jing Wang, Kenneth N. Goldie, Rosmarie Sütterlin, Daniel Castaño-Díez, Paula Pérez-Navarro, Evelien Huisman, Sabine Ipsen, Angela Ingrassia, Yvonne de Gier, Annemieke J.M. Rozemuller, Anne De Paepe, Johannes Erny, Andreas Staempfli, Joerg Hoernschemeyer, Frederik Großerüschkamp, Daniel Niedieker, Samir F. El-Mashtoly, Marialuisa Quadri, Wilfred F.J. van IJcken, Vincenzo Bonifati, Klaus Gerwert, Bernd Bohrmann, Stephan Frank, Markus Britschgi, Henning Stahlberg, Wilma D. J. van de Berg, Matthias E. Lauer
bioRxiv 137976; doi: https://doi.org/10.1101/137976
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Lewy pathology in Parkinson’s disease consists of a crowded organellar membranous medley
Sarah H. Shahmoradian, Christel Genoud, Alexandra Graff-Meyer, Jürgen Hench, Tim Moors, Gabriel Schweighauser, Jing Wang, Kenneth N. Goldie, Rosmarie Sütterlin, Daniel Castaño-Díez, Paula Pérez-Navarro, Evelien Huisman, Sabine Ipsen, Angela Ingrassia, Yvonne de Gier, Annemieke J.M. Rozemuller, Anne De Paepe, Johannes Erny, Andreas Staempfli, Joerg Hoernschemeyer, Frederik Großerüschkamp, Daniel Niedieker, Samir F. El-Mashtoly, Marialuisa Quadri, Wilfred F.J. van IJcken, Vincenzo Bonifati, Klaus Gerwert, Bernd Bohrmann, Stephan Frank, Markus Britschgi, Henning Stahlberg, Wilma D. J. van de Berg, Matthias E. Lauer
bioRxiv 137976; doi: https://doi.org/10.1101/137976

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