PT  - JOURNAL ARTICLE
AU  - Stefan Grathwohl
AU  - Emmanuel Quansah
AU  - Nazia Maroof
AU  - Jennifer A. Steiner
AU  - Liz Spycher
AU  - Fethallah Benmansour
AU  - Gonzalo Duran-Pacheco
AU  - Juliane Siebourg-Polster
AU  - Krisztina Oroszlan-Szovik
AU  - Helga Remy
AU  - Markus Haenggi
AU  - Marc Stawiski
AU  - Matthias Sehlhausen
AU  - Pierre Maliver
AU  - Andreas Wolfert
AU  - Thomas Emrich
AU  - Zachary Madaj
AU  - Martha L. Escobar Galvis
AU  - Christoph Mueller
AU  - Annika Herrmann
AU  - Patrik Brundin
AU  - Markus Britschgi
TI  - Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology
AID  - 10.1101/505164
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 505164
4099  - http://biorxiv.org/content/early/2019/03/20/505164.short
4100  - http://biorxiv.org/content/early/2019/03/20/505164.full
AB  - 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.