Gut mucosal cells transfer α-synuclein to the vagus nerve

Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson’s disease (PD). While past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut to brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of the gut mucosa express α-synuclein. In this study, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from gut epithelial cells in organoids co-cultured with vagal nodose neurons that are otherwise devoid of α-synuclein expression. In intact mice that express pathological human α-synuclein, but no mouse α-synuclein, α-synuclein fibril templating activity emerges in α-synuclein seeded fibril aggregation assays in tissues from the gut, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfers to the vagus nerve and to the dorsal motor nucleus. Subdiaphragmatic vagotomy prior to the induction of α-synuclein expression in the gut epithelial cells effectively protects the hindbrain from the emergence of α-synuclein fibril templating activity. Overall, these findings highlight a novel potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.