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Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology

Stefan Grathwohl, Emmanuel Quansah, Nazia Maroof, Jennifer A. Steiner, Liz Spycher, Fethallah Benmansour, Gonzalo Duran-Pacheco, Juliane Siebourg-Polster, Krisztina Oroszlan-Szovik, Helga Remy, Markus Haenggi, Marc Stawiski, Matthias Sehlhausen, Pierre Maliver, Andreas Wolfert, Thomas Emrich, Zachary Madaj, Martha L. Escobar Galvis, Christoph Mueller, Annika Herrmann, Patrik Brundin, View ORCID ProfileMarkus Britschgi
doi: https://doi.org/10.1101/505164
Stefan Grathwohl
1Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Emmanuel Quansah
2Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, USA
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Nazia Maroof
1Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Jennifer A. Steiner
2Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, USA
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Liz Spycher
1Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Fethallah Benmansour
3Roche Pharma Research and Early Development, pREDi, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Gonzalo Duran-Pacheco
4Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Juliane Siebourg-Polster
4Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Krisztina Oroszlan-Szovik
1Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Helga Remy
1Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Markus Haenggi
1Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Marc Stawiski
1Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Matthias Sehlhausen
4Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Pierre Maliver
4Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Andreas Wolfert
5Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany
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Thomas Emrich
5Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany
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Zachary Madaj
2Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, USA
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Martha L. Escobar Galvis
2Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, USA
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Christoph Mueller
6Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, Switzerland
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Annika Herrmann
4Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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Patrik Brundin
2Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, USA
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Markus Britschgi
1Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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  • ORCID record for Markus Britschgi
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Abstract

Intraneuronal accumulation of α-synuclein (αSyn) is key in the pathogenesis of Parkinson’s disease (PD). Published studies suggest that this process begins in the enteric nervous system (ENS) and propagates into the brain decades before clinical diagnosis of PD. The triggers and mechanisms underlying the accumulation of αSyn remain unknown but evidence is growing that immune pathways and in particular colitis may play a critical role. Here we demonstrate that patients with inflammatory bowel disease (IBD) exhibit αSyn accumulation in their colon. We then confirmed in an experimental model of IBD that intestinal inflammation can trigger αSyn accumulation in the ENS of wildtype and αSyn transgenic mice. We discovered that the type and degree of inflammation modulates the extent of αSyn accumulation in the colon and that macrophage-related signaling limits this process. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain, including the substantia nigra, in 21-month but not 9-month-old αSyn transgenic mice. This was accompanied by loss of nigral tyrosine hydroxylase-immunoreactive neurons, another neuropathological hallmark of PD. Together, our data suggest a critical role for intestinal inflammation in the initiation and progression of PD.

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Posted March 20, 2019.
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Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology
Stefan Grathwohl, Emmanuel Quansah, Nazia Maroof, Jennifer A. Steiner, Liz Spycher, Fethallah Benmansour, Gonzalo Duran-Pacheco, Juliane Siebourg-Polster, Krisztina Oroszlan-Szovik, Helga Remy, Markus Haenggi, Marc Stawiski, Matthias Sehlhausen, Pierre Maliver, Andreas Wolfert, Thomas Emrich, Zachary Madaj, Martha L. Escobar Galvis, Christoph Mueller, Annika Herrmann, Patrik Brundin, Markus Britschgi
bioRxiv 505164; doi: https://doi.org/10.1101/505164
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Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology
Stefan Grathwohl, Emmanuel Quansah, Nazia Maroof, Jennifer A. Steiner, Liz Spycher, Fethallah Benmansour, Gonzalo Duran-Pacheco, Juliane Siebourg-Polster, Krisztina Oroszlan-Szovik, Helga Remy, Markus Haenggi, Marc Stawiski, Matthias Sehlhausen, Pierre Maliver, Andreas Wolfert, Thomas Emrich, Zachary Madaj, Martha L. Escobar Galvis, Christoph Mueller, Annika Herrmann, Patrik Brundin, Markus Britschgi
bioRxiv 505164; doi: https://doi.org/10.1101/505164

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