In a mouse alpha-synuclein PFF model, aged wild-type mice develop a type I interferon–dependent gastrointestinal inflammatory response that is absent in IFNAR1 knockout animals and is recapitulated in intestinal organoids via enteroendocrine uptake of α‑syn, implicating IFN signaling in gut-brain…

Points to type I IFN/IFNAR1 signaling as a actionable, targetable mechanism linking brain α‑syn pathology to gut inflammation, supporting therapeutic strategies (e.g., IFNAR blockade or JAK inhibition) to limit PD progression along the gut–brain axis.

BACKGROUND AND AIMS: Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized 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 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. METHODS: Young (10-12 weeks) and aged (40-50 weeks) wild-type and IFN alpha receptor (IFNAR)1-/- mice received an intrastriatal injection of human alpha-synuclein (α-syn) preformed fibrils (PFFs) (8 ug) with gut tissue analyzed 6 months postinjection. A mouse intestinal organoid culture model was established to further characterize the α-syn-induced inflammatory response in the gut. RESULTS: An intrastriatal injection of human α-syn PFFs was shown to initiate a type I IFN-dependent neuroinflammatory response in the gastrointestinal tract of wild-type mice at 6 months postinjection. This response was attributed to an elevation in type I IFN signaling in aged mice that was absent in the IFNAR1-/- mice. Mouse intestinal organoid cultures confirmed α-syn was taken up by the enteroendocrine cells to induce a type I IFN-mediated pro-inflammatory response that was attenuated in IFNAR1-/- cultures. CONCLUSION: This study has confirmed the type I IFNs modulate the α-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.