Gut mucosal cells transfer -synuclein to the vagus nerve

Epidemiological and histopathological findings have raised the possibility that misfolded alpha-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson's disease. Although past experimental studies in mouse models have relied on gut injections of exogenous recombinant alpha-synuclein fibrils to study gut-to-brain alpha-synuclein transfer, the possible origins of misfolded alpha-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of intestinal mucosa express alpha-synuclein. Here, we employed mouse intestinal organoids expressing human alpha-synuclein to observe the transfer of alpha-synuclein protein from epithelial cells in organoids to cocultured nodose neurons devoid of alpha-synuclein. In mice expressing human alpha-synuclein, but no mouse alpha-synuclein, alpha-synuclein fibril-templating activity emerged in alpha-synuclein-seeded fibril aggregation assays in intestine, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human alpha-synuclein expression to intestinal epithelial cells, alpha-synuclein fibril-templating activity transfered to the vagus nerve and dorsal motor nucleus. Subdiaphragmatic vagotomy prior to induction of alpha-synuclein expression in intestinal epithelial cells effectively protected the hindbrain from emergence of alpha-synuclein fibriltemplating activity. Overall, these findings highlight a potential non-neuronal source of fibrillar alpha-synuclein protein that might arise in gut mucosal cells.