IL-1β/IL-1R1 signaling in the GIT regulates alpha-synuclein pathology and its propagation to the brain.

Abstract Accumulating evidence suggests that inflammatory bowel disease and misfolded alpha-synuclein (αsyn) of the gut are often found in Parkinson's disease (PD). However, the relationship between gastrointestinal inflammation with α-syn pathology and PD development is unknown. It is hypothesized that the α-syn pathology induced by gastrointestinal inflammation can begin in the enteric neural cells (ENS) of the gastrointestinal tract (GIT) and then propagate to the brain. To test this hypothesis, oral administration of rotenone (ROT) was used to induce GIT inflammation. PD-like responses were studied by histochemical and behavioral examinations in mice. Results show that the ROT treatments rendered macrophage activation, inflammatory mediator expression, and α-syn pathology in the GIT six weeks after the treatment. Pathological α-syn, namely pS129- α-syn, was found to be localized with IL-1R1 positive neural cells, which were transferred to the dorsal motor vagus (DMV) region via the vagus nerve. In addition, microglial activation and α-syn pathology (pS129- α-syn) in the ENS, DMV, and SN regions were observed in an interleukin-1β (IL-1β)/IL-1 receptor type I (IL-1R1) dependent. These results, therefore, reveal that inflammation of GIT can induce αsyn pathology and that IL-1β/IL-1R1-dependent propagation of α-syn via vagus nerve could lead to PD development.