Background : Intraneuronal accumulation of a-synuclein (αSyn) is key in Parkinson’s disease (PD) pathogenesis. The pathogenic process is suggested to begin in the enteric nervous system decades before diagnosis of PD and then propagate into the brain. The triggers for these events are unclear but, in some patients, colitis might play a critical role.
Methods : We administered lipopolysaccharide (LPS) or dextran sulfate sodium (DSS) to assess the effect of different types of experimental colitis on αSyn accumulation in the gut of αSyn transgenic and wild type mice and quantified local gene expression by RT-PCR and level of αSyn accumulation by immunofluorescence imaging. Immune modulation during the DSS colitis paradigm in the αSyn transgenic mice included genetic ablation of Cx3cr1 or treatment with recombinant IL-10. To determine long-term effects of experimental colitis, we induced DSS colitis in young αSyn transgenic mice and aged them under normal conditions up to nine or 21 months before analyzing their brains by immunohistochemistry. In vivo experiments were performed in randomized cohorts. Blinded experimenters performed image analysis and statistical analysis depended on data type (i.e., Student’s t-test, ANOVA, mixed-effects model).
Results : We demonstrate that mild sustained or one strong insult of experimental DSS colitis triggers αSyn accumulation in the submucosal plexus of wild type and αSyn transgenic mice, while short-term mild DSS experimental colitis or inflammation induced by LPS does not have such an effect. Lack of macrophage-related Cx3cr1-signalling during DSS colitis increases accumulation of αSyn in the colonic submucosal plexus of αSyn transgenic mice while systemic treatment with immune-dampening IL-10 ameliorates this phenomenon. Additionally, DSS colitis-induced αSyn accumulation in young αSyn transgenic mice persists for months and is exacerbated by lack of Cx3cr1-signaling. Remarkably, experimental colitis at three months of age exacerbates the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain (including the substantia nigra), in 21- but not 9-month-old αSyn transgenic mice. This increase in midbrain αSyn accumulation is accompanied by the loss of tyrosine hydroxylase-immunoreactive nigral neurons.
Conclusions : Our data suggest that specific types of intestinal inflammation, mediated by monocyte/macrophage signaling, could play a critical role in the initiation and progression of PD.