RT Journal Article
SR Electronic
T1 Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 505164
DO 10.1101/505164
A1 Grathwohl, Stefan
A1 Quansah, Emmanuel
A1 Maroof, Nazia
A1 Steiner, Jennifer A.
A1 Spycher, Liz
A1 Benmansour, Fethallah
A1 Duran-Pacheco, Gonzalo
A1 Siebourg-Polster, Juliane
A1 Oroszlan-Szovik, Krisztina
A1 Remy, Helga
A1 Haenggi, Markus
A1 Stawiski, Marc
A1 Sehlhausen, Matthias
A1 Maliver, Pierre
A1 Wolfert, Andreas
A1 Emrich, Thomas
A1 Madaj, Zachary
A1 Galvis, Martha L. Escobar
A1 Mueller, Christoph
A1 Herrmann, Annika
A1 Brundin, Patrik
A1 Britschgi, Markus
YR 2019
UL http://biorxiv.org/content/early/2019/03/20/505164.abstract
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.