INFLAMMATORY BOWEL DISEASE INDUCES α-SYNUCLEIN AGGREGATION IN GUT AND BRAIN

Espinosa-Oliva, A. M.; Laza, R. R.; Soto, M. S.; Serrano, A. B.; Perez, A. I. R.; Ceballos, M. A. R.; Revilla, J. G.; Pavon, M. S.; Serres, S.; Economopoulus, V.; Vazquez, A. E. C.; Carretero, M. D. V.; Miranda, P. G.; Klementieva, O.; Martin, M. J. O.; Deierborg, T.; Infante, E. R.; Sibson, N. R.; Garcia, J. L. L.; de la Quintana, A. M.; Rubio, M. J. P.; Carmona, A. J. H.; Recio, J. L. V.; de Pablos, R. M.

doi:10.1101/2022.01.26.477259

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bioRxiv · 10.1101/2022.01.26.477259

INFLAMMATORY BOWEL DISEASE INDUCES α-SYNUCLEIN AGGREGATION IN GUT AND BRAIN

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Abstract

According to Braaks hypothesis, it is plausible that Parkinso[n]s disease (PD) starts in the enteric nervous system (ENS) to spread the brain via the vagus nerve. Thus, we were wondering whether human inflammatory bowel diseases (IBD) can progress with appearance of pathogenic -synuclein (-syn) in the gastrointestinal tract and midbrain dopaminergic neurons. Analysis of human gastrointestinal tract sections from IBD patients demonstrated the presence of pathogenic phosphorylated -syn in both myenteric (Auerbachs) and submucosal (Meissners) plexuses. Remarkably, PD subjects exhibit -syn pathology in identical gastrointestinal locations. Analysis of human midbrain sections from IBD subjects revealed a clear displacement of neuromelanin in some nigral neurons from the ventral mesencephalon, which were inherently associated with presence of -syn aggregates reminiscent of pale bodies. We also used different dextran sodium sulfate (DSS)-based rat models of gut inflammation (subchronic and chronic) to study the appearance of phosphorylated -syn inclusions in both Auerbachs and Meissners plexuses (gut), and in dopaminergic neuritic processes (brain) along with degeneration of nigral dopaminergic neurons, which are considered classical hallmarks of PD. Vagotomized DSS-treated animals exhibited pathological -syn in the gut but failed to show dopaminergic cells degeneration and -syn aggregation in the ventral mesencephalon. Taken together, these results strongly suggest that Braaks hypothesis is plausible.

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Espinosa-Oliva, A. M., Laza, R. R., Soto, M. S., Serrano, A. B., Perez, A. I. R., Ceballos, M. A. R., Revilla, J. G., Pavon, M. S., Serres, S., Economopoulus, V., Vazquez, A. E. C., Carretero, M. D. V., Miranda, P. G., Klementieva, O., Martin, M. J. O., Deierborg, T., Infante, E. R., Sibson, N. R., Garcia, J. L. L., de la Quintana, A. M., Rubio, M. J. P., Carmona, A. J. H., Recio, J. L. V., de Pablos, R. M.. 2022-01-28. INFLAMMATORY BOWEL DISEASE INDUCES α-SYNUCLEIN AGGREGATION IN GUT AND BRAIN. https://doi.org/10.1101/2022.01.26.477259

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