IL-1/IL-1R1 signaling is involved in the propagation of -synuclein pathology of the gastrointestinal tract to the brain

The pathological hallmark of Parkinson's disease (PD) is the intraneuronal accumulation of misfolded alpha-synuclein (termed Lewy bodies) in dopaminergic neurons of substantia nigra par compacta (SNc). It is assumed that the alpha-syn pathology is induced by gastrointestinal inflammation and then transfers to the brain by the gut-brain axis. Therefore, the relationship between gastrointestinal inflammation and alpha-syn pathology leading to PD remains to be investigated. In our study, rotenone (ROT) oral administration induces gastrointestinal tract (GIT) inflammation in mice. In addition, we used pseudorabies virus (PRV) for tracing studies and performed behavioral testing. We observed that ROT treatments enhance macrophage activation, inflammatory mediator expression, and alpha-syn pathology in the GIT 6-week post-treatment (P6). Moreover, pathological alpha-syn was localized with IL-1R1 positive neural cells in GIT. In line with these findings, we also find pS129-alpha-syn signals in the dorsal motor nucleus of the vagus (DMV) and tyrosine hydroxylase in the nigral-striatum dynamically change from 3-week post-treatment (P3) to P6. Following that, pS129-alpha-syn was dominant in the enteric neural cell, DMV, and SNc, accompanied by microglial activation, and these phenotypes were absent in IL-1R1(r/r) mice. These data suggest that IL-1 beta/IL-1R1-dependent inflammation of GIT can induce a-syn pathology, which then propagates to the DMV and SNc, resulting in PD.