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, and Markus Britschgi

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Received date 28th April 19

Intraneuronal a-synuclein accumulation is key in Parkinson’s disease (PD) pathogenesis. The pathogenic process is suggested to begin in the enteric nervous system and propagate into the brain already decades before diagnosis of PD.  In some patients, colitis might play a critical role in this process. Here we demonstrate that patients with inflammatory bowel disease exhibit a-synuclein accumulation in the colon and that experimental colitis triggers a-synuclein accumulation in certain enteric nerves of mice. The type and degree of experimental inflammation modulates the extent of colonic a-synuclein accumulation and macrophage-related signaling limits this process. Remarkably, experimental colitis at three months of age exacerbates the accumulation of aggregated phospho-Serine 129 a-synuclein in the midbrain (including the substantia nigra), in 21- but not 9-month-old a-synuclein transgenic mice. This is accompanied by loss of tyrosine hydroxylase-immunoreactive nigral neurons. Our data suggest that intestinal inflammation might play a critical role in the initiation and progression of PD.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature