Specific immune modulation of experimental colitis drives enteric alpha-synuclein accumulation and triggers age-related Parkinson-like brain pathology

Authors

  • Stefan Grathwohl Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Emmanuel Quansah Parkinson’s Disease Center, Department of Neurodegenerative Science, Van Andel Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, USA
  • Nazia Maroof Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Jennifer A. Steiner Parkinson’s Disease Center, Department of Neurodegenerative Science, Van Andel Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, USA
  • Liz Spycher Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Fethalla Benmansour Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Gonzalo Duran-Pacheco Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Juliane Siebourg-Polster Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Krisztina Oroszlan-Szovik Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Helga Remy Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Markus Haenggi Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Marc Stawiski Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Matthias Selhausen Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Pierre Mailver Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Andreas Wolfert Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, Penzberg, Germany
  • Thomas Emrich Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, Penzberg, Germany
  • Zachary Madaj Parkinson’s Disease Center, Department of Neurodegenerative Science, Van Andel Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, USA
  • Arel Su Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Martha L. Escobar Galvis Parkinson’s Disease Center, Department of Neurodegenerative Science, Van Andel Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, USA
  • Christoph Mueller Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, Switzerland
  • Annika Herrmann Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
  • Patrik Brundin Parkinson’s Disease Center, Department of Neurodegenerative Science, Van Andel Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, USA
  • Markus Britschgi Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland

DOI:

https://doi.org/10.17879/freeneuropathology-2021-3326

Keywords:

Alpha-synuclein, Experimental colitis, Enteric nervous system, Parkinson's disease, Substantia nigra

Abstract

Background: In some people with Parkinson’s disease (PD), a-synuclein (αSyn) accumulation may begin in the enteric nervous system (ENS) decades before development of brain pathology and disease diagnosis.

Objective: To determine how different types and severity of intestinal inflammation could trigger αSyn accumulation in the ENS and the subsequent development of αSyn brain pathology.

Methods: We assessed the effects of modulating short- and long-term experimental colitis on αSyn accumulation in the gut of αSyn transgenic and wild type mice by immunostaining and gene expression analysis. To determine the long-term effect on the brain, we induced dextran sulfate sodium (DSS) colitis in young αSyn transgenic mice and aged them under normal conditions up to 9 or 21 months before tissue analyses.

Results: A single strong or sustained mild DSS colitis triggered αSyn accumulation in the submucosal plexus of wild type and αSyn transgenic mice, while short-term mild DSS colitis or inflammation induced by lipopolysaccharide did not have such an effect. Genetic and pharmacological modulation of macrophage-associated pathways modulated the severity of enteric αSyn. 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- but not 9-month-old αSyn transgenic mice. This increase in midbrain αSyn accumulation is accompanied by the loss of tyrosine hydroxylase-immunoreactive nigral neurons.

Conclusions: Our data suggest that specific types and severity of intestinal inflammation, mediated by monocyte/macrophage signaling, could play a critical role in the initiation and progression of PD.

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Published

2021-05-18

How to Cite

Grathwohl, S., Quansah, E., Maroof, N., Steiner, J. A., Spycher, L., Benmansour, F., Duran-Pacheco, G., Siebourg-Polster, J., Oroszlan-Szovik, K., Remy, H., Haenggi, M., Stawiski, M., Selhausen, M., Mailver, P., Wolfert, A., Emrich, T., Madaj, Z., Su, A., Escobar Galvis, M. L., Mueller, C., Herrmann, A., Brundin, P., & Britschgi, M. (2021). Specific immune modulation of experimental colitis drives enteric alpha-synuclein accumulation and triggers age-related Parkinson-like brain pathology. Free Neuropathology, 2, 13. https://doi.org/10.17879/freeneuropathology-2021-3326

Issue

Vol. 2 (2021)

Section

Original Papers

License

Papers are published open access under the Creative Commons BY 4.0 license. This license lets others distribute, remix, adapt, and build upon your work, even commercially, as long as they credit you for the original creation. Data included in the article are made available under the CC0 1.0 Public Domain Dedication waiver, unless otherwise stated, meaning that all copyrights are waived.