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

  • 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
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.

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
Section
Original Papers