Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology

Grathwhohl, 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.; Sehlhausen, M.; Maliver, P.; Wolfert, A.; Emrich, T.; Madaj, Z.; Escobar Galvis, M. L.; Mueller, C.; Herrnann, A.; Brundin, P.; Britschgi, M.

doi:10.1101/505164

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bioRxiv · 10.1101/505164

Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology

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Abstract

Intraneuronal accumulation of -synuclein (Syn) is key in the pathogenesis of Parkinsons 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 Syn 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 Syn accumulation in their colon. We then confirmed in an experimental model of IBD that intestinal inflammation can trigger Syn accumulation in the ENS of wildtype and Syn transgenic mice. We discovered that the type and degree of inflammation modulates the extent of Syn 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 Syn in the midbrain, including the substantia nigra, in 21-month but not 9-month-old Syn 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.

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Grathwhohl, 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., Sehlhausen, M., Maliver, P., Wolfert, A., Emrich, T., Madaj, Z., Escobar Galvis, M. L., Mueller, C., Herrnann, A., Brundin, P., Britschgi, M.. 2018-12-22. Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology. https://doi.org/10.1101/505164

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