Kristopher SCHMIT

Alpha-synuclein-induced patholigies in brain and gut by curli and a fibre-deprived diet in a transgenic mouse model of Parkinson’s disease

Parkinson’s disease (PD) is a complex, multi-factorial disease for which multiple mechanisms have been postulated contribute to its physiopathology. We hypothesize that PD can be triggered and driven by a combinatorial effect of reduced gut barrier function driven by microbial mucus foraging due to dietary caused microbiome imbalance and exposure to bacterial amyloidogenic peptides that initiate alpha-synuclein (aSyn) aggregation and prion-like propagation from the PNS to the CNS.
We performed motor behaviour, neuro- and GI pathology and 16S amplicon sequencing on transgenic human aSyn mice and their wild-type littermates, which were fed a fibre deprived diet or normal chow, while gavage with either curli expressing wild-type or isogenic curli-operon knock-out E.coli strains or PBS for 9 weeks.
Transgenic animals, which were exposed to both the FD diet and the curli-producing bacteria showed decline in movement coordination. Animals on FD diet manifest dysbiosis (e.g. increase of A.muciniphila) and significant outer mucus thinning of the colon. Further, neuropathological results show a subtle, but consistent, pattern of neurodegeneration and aSyn aggregation across different PD relevant areas in transgenic animals exposed to curli-producing bacteria, exacerbated by dietary fibre deprivation.
Our results indicate that a series of factors, including environmental ones (e.g. diet) acting through the gut, can precipitate PD-like pathologies in a mouse model, thus suggesting that proper life style choices may help PD patients slow their disease process.

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