Gut mucosal cells transfer α-synuclein to the vagus nerve

Abstract

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 Parkinsons disease (PD). While 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 the gut mucosa express alpha-synuclein. In this study, we employed mouse intestinal organoids expressing human alpha-synuclein to observe the transfer of alpha-synuclein protein from gut epithelial cells in organoids co-cultured with vagal nodose neurons that are otherwise devoid of alpha-synuclein expression. In intact mice that express pathological human alpha-synuclein, but no mouse alpha;-synuclein, alpha-synuclein fibril templating activity emerges in alpha-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 alpha-synuclein expression to intestinal epithelial cells, alpha-synuclein fibril-templating activity transfers to the vagus nerve and to the dorsal motor nucleus. Subdiaphragmatic vagotomy prior to the induction of alpha-synuclein expression in the gut epithelial cells effectively protects the hindbrain from the emergence of alpha-synuclein fibril templating activity. Overall, these findings highlight a novel potential non-neuronal source of fibrillar alpha-synuclein protein that might arise in gut mucosal cells.

Therapeutics for neurodegenerative diseases by targeting the gut microbiome: from bench to bedside

“…In AD and PD, Aβ and α-synuclein are deposited not only in the brain but also in the gut [ 72 – 74 ]. A variety of amyloid-producing bacteria in the gut can trigger amyloid accumulation, and these nonhuman amyloids with prion-like properties can undergo retrograde translocation to the brain via the enteric nerve and the vagus nerve [ 75 – 77 ]. Additionally, gut microbiome-derived extracellular vesicles can penetrate both intestinal epithelium and vascular endothelium, and enter host cells through endocytosis [ 78 ].…”

Stem Cell-Based Approaches in Parkinson’s Disease Research

“…These aspects are linked to the limitations of the OASIS model, which, despite its ability to mimic α-syn aggregation, is confined to representing the molecular phenotype at the endpoint of cellular pathology. The model faces limitations in depicting the cellular pathological mechanisms initiating PD, including the recently investigated propagation of misfolded α-syn in the gut-brain axis and functional impairment due to misfolded α-syn within cells (155,156). Falling short, the model fails to capture the broader molecular pathological mechanisms occurring before α-syn aggregation, such as issues stemming from a low functional protein dose of α-syn (157) and dominant-negative mutants (158) caused by α-syn mutations (159,160).…”