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bioRxiv · 10.1101/2024.05.05.592614

Type-I interferons drive the gastrointestinal inflammatory response in a mouse model of Parkinsons disease

Waters, H.·Chen, S.·Vincan, E.·Flanagan, D. J.·Schwab, R. H. M.·Crack, P. J.·Taylor, J. M.
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Abstract

Background and AimsParkinsons disease (PD) is an age-related neurodegenerative disorder characterised by classical motor symptoms due to a loss of dopaminergic neurons in the substantia nigra pars compacta. The type-I interferons (IFNs) are elevated in the aging brain and we have implicated them in the neuroinflammatory response in PD. With increasing evidence of gastrointestinal (GI) dysfunction in PD patients, this study explored the contribution of the type-I IFNs to the transmission of pathology from the brain to the gut in PD. MethodsYoung (10-12 weeks) and aged (40-50 weeks) wildtype and IFNAR1-/- mice received an intrastriatal injection of human alpha-synuclein (-Syn) pre-formed fibrils (PFF) (8ug) with gut tissue analysed 6-months post-injection (p.i). A mouse intestinal organoid culture model was established to further characterise the -Syn induced inflammatory response in the gut. ResultsAn intrastriatal injection of human -Syn PFFs was shown to initiate a type-I IFN-dependent neuroinflammatory response in the GI tract of wildtype mice at 6-months p.i. This response was attributed to an elevation in type-I IFN signalling in aged mice that was absent in the IFNAR1-/- mice. Mouse intestinal organoid cultures confirmed -Syn was taken up by the enteroendocrine cells (EECs) to induce a type-I IFN mediated pro-inflammatory response that was attenuated in IFNAR1-/- cultures. ConclusionThis study has confirmed the type-I IFNs modulate the -Syn PFF induced inflammatory response within the gut potentiating pathology progression along the gut-brain axis. Early intervention of this type-I IFN response may be a potential therapeutic target to limit the progression of PD.

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Waters, H., Chen, S., Vincan, E., Flanagan, D. J., Schwab, R. H. M., Crack, P. J., Taylor, J. M.. 2024-05-07. Type-I interferons drive the gastrointestinal inflammatory response in a mouse model of Parkinsons disease. https://doi.org/10.1101/2024.05.05.592614

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