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Although past experimental studies in mouse models have relied on gut injections of exogenous recombinant \u03b1-synuclein fibrils to study gut-to-brain \u03b1-synuclein transfer, the possible origins of misfolded \u03b1-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of intestinal mucosa express \u03b1-synuclein. Here, we employed mouse intestinal organoids expressing human \u03b1-synuclein to observe the transfer of \u03b1-synuclein protein from epithelial cells in organoids to cocultured nodose neurons devoid of \u03b1-synuclein. In mice expressing human \u03b1-synuclein, but no mouse \u03b1-synuclein, \u03b1-synuclein fibril-templating activity emerged in \u03b1-synuclein\u2013seeded fibril aggregation assays in intestine, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human \u03b1-synuclein expression to intestinal epithelial cells, \u03b1-synuclein fibril-templating activity transfered to the vagus nerve and dorsal motor nucleus. Subdiaphragmatic vagotomy prior to induction of \u03b1-synuclein expression in intestinal epithelial cells effectively protected the hindbrain from emergence of \u03b1-synuclein fibril-templating activity. Overall, these findings highlight a potential non-neuronal source of fibrillar \u03b1-synuclein protein that might arise in gut mucosal cells.<\/jats:p>","DOI":"10.1172\/jci.insight.172192","type":"journal-article","created":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T14:00:47Z","timestamp":1701957647000},"source":"Crossref","is-referenced-by-count":64,"title":["Gut mucosal cells transfer \u03b1-synuclein to the vagus nerve"],"prefix":"10.1172","volume":"8","author":[{"given":"Rashmi","family":"Chandra","sequence":"first","affiliation":[{"name":"Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arpine","family":"Sokratian","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cancer Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine R.","family":"Chavez","sequence":"additional","affiliation":[{"name":"Department of 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