Gut Bacterial Infection Triggers Parkinson's-Like Pathology in Mice Carrying LRRK2 Mutation
Researchers found that mice carrying the LRRK2 G2019S Parkinson's risk mutation developed progressive Parkinson's-like neurodegeneration after repeated gut bacterial infections, while normal mice remained largely unaffected. The LRRK2 G2019S mutation is one of the most common genetic risk factors for Parkinson's disease in humans, but had not previously been shown to cause robust neurodegeneration in mice without an additional environmental trigger. The findings support a gut-brain axis model in which recurrent intestinal inflammation, amplified by a genetic predisposition, may drive the onset of Parkinson's disease.
A new preprint study published on bioRxiv used a mouse model to demonstrate that the LRRK2 G2019S genetic mutation — a well-known Parkinson's disease risk factor — acts as a sensitizing factor that, when combined with recurrent gut bacterial infection, produces hallmark features of Parkinson's disease. Mice carrying the mutation were repeatedly infected with Citrobacter rodentium, a bacterium that causes intestinal inflammation in rodents, and subsequently developed motor impairment, reduced locomotor activity, loss of dopamine-producing neurons in the nigrostriatal pathway, neuroinflammation, and accumulation of pathological phosphorylated alpha-synuclein. Wild-type mice subjected to the same infections showed little to no such pathology. Mechanistically, the mutant mice showed exacerbated colonic inflammation, a breakdown of the intestinal barrier, and heightened inflammasome activation, even though they cleared the bacteria normally — suggesting the mutation amplifies inflammatory signaling rather than impairing immune defense. Critically, pathological alpha-synuclein accumulated in the gut and spread beyond the intestinal epithelium in mutant mice, consistent with the hypothesis that gut-originating pathology can travel to the brain via the gut-brain axis. The study establishes a physiologically relevant gene-environment interaction model that may help explain why only a subset of LRRK2 mutation carriers develop Parkinson's disease.
What's missing
As a preprint, this study has not yet undergone peer review. The model uses Citrobacter rodentium, which does not naturally infect humans; whether analogous recurrent gut infections in humans with the LRRK2 G2019S mutation produce similar effects remains untested. The proportion of human LRRK2 G2019S carriers who experience recurrent enteric infections sufficient to trigger this pathway is unknown.
What different sources said
- bioRxivCenter
Gut bacterial Infection drives Parkinsonian pathology in LRRK2 G2019S Knock-in Mice
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