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α-Synuclein polymorphism determines oligodendroglial dysfunction

View ORCID ProfileBenedikt Frieg, View ORCID ProfileJames A. Geraets, Timo Strohäker, View ORCID ProfileChristian Dienemann, View ORCID ProfilePanagiota Mavroeidi, Byung Chul Jung, View ORCID ProfileWoojin S. Kim, Seung-Jae Lee, View ORCID ProfileMaria Xilouri, View ORCID ProfileMarkus Zweckstetter, View ORCID ProfileGunnar F. Schröder
doi: https://doi.org/10.1101/2021.07.09.451731
Benedikt Frieg
1Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, Jülich, Germany
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James A. Geraets
1Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, Jülich, Germany
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Timo Strohäker
2German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075 Göttingen, Germany
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Christian Dienemann
3Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077 Göttingen, Germany
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Panagiota Mavroeidi
4Center of Clinical, Experimental Surgery, & Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA) 4, Soranou Efesiou Street, Athens 11527, Greece
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Byung Chul Jung
5Department of Biomedical Sciences, Neuroscience Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea
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Woojin S. Kim
6Brain and Mind Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
7School of Medical Sciences, University of New South Wales & Neuroscience Research Australia, Randwick NSW 2031, Australia
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Seung-Jae Lee
5Department of Biomedical Sciences, Neuroscience Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea
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Maria Xilouri
4Center of Clinical, Experimental Surgery, & Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA) 4, Soranou Efesiou Street, Athens 11527, Greece
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Markus Zweckstetter
2German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075 Göttingen, Germany
8Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077 Göttingen, Germany
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  • For correspondence: gu.schroeder@fz-juelich.de mazw@nmr.mpibpc.mpg.de
Gunnar F. Schröder
1Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, Jülich, Germany
9Physics Department, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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  • For correspondence: gu.schroeder@fz-juelich.de mazw@nmr.mpibpc.mpg.de
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Abstract

Synucleinopathies, such as Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are progressive and unremitting neurological diseases. For both PD and MSA, α-synuclein fibril inclusions inside brain cells are neuropathological hallmarks. In addition, amplification of α-synuclein fibrils from body fluids is a potential biomarker distinguishing PD from MSA. However, little is known about the structure of α-synuclein fibrils amplified from human samples and its connection to α-synuclein fibril structure in the human brain. Here we amplified α-synuclein fibrils from PD and MSA brain tissue, characterized its seeding potential in oligodendroglia, and determined the 3D structures by cryo-electron microscopy. We show that the α-synuclein fibrils from a MSA patient are more potent in recruiting the endogenous α-synuclein and evoking a redistribution of TPPP/p25α protein in mouse primary oligoden-droglial cultures compared to those amplified from a PD patient. Cryo-electron microscopy shows that the PD- and MSA-amplified α-synuclein fibrils share a similar protofilament fold but differ in their inter-protofilament interface. The structures of the brain-tissue amplified α-synuclein fibrils are also similar to other in vitro and ex vivo α-synuclein fibrils. Together with published data, our results suggest that αSyn fibrils differ between PD and MSA in their quaternary arrangement and could further vary between different forms of PD and MSA.

Competing Interest Statement

S.-J.L. is a founder and co-CEO of Neuramedy Co., Ltd. The other authors declare no competing interests.

Copyright 
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 July 10, 2021.
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α-Synuclein polymorphism determines oligodendroglial dysfunction
Benedikt Frieg, James A. Geraets, Timo Strohäker, Christian Dienemann, Panagiota Mavroeidi, Byung Chul Jung, Woojin S. Kim, Seung-Jae Lee, Maria Xilouri, Markus Zweckstetter, Gunnar F. Schröder
bioRxiv 2021.07.09.451731; doi: https://doi.org/10.1101/2021.07.09.451731
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α-Synuclein polymorphism determines oligodendroglial dysfunction
Benedikt Frieg, James A. Geraets, Timo Strohäker, Christian Dienemann, Panagiota Mavroeidi, Byung Chul Jung, Woojin S. Kim, Seung-Jae Lee, Maria Xilouri, Markus Zweckstetter, Gunnar F. Schröder
bioRxiv 2021.07.09.451731; doi: https://doi.org/10.1101/2021.07.09.451731

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