Abstract Intraneuronal accumulation of α-synuclein (αSyn) is key in the pathogenesis of Parkinson’s disease (PD). Published studies suggest that this process begins in the enteric nervous system (ENS) and propagates into the brain decades before clinical diagnosis of PD. The triggers and mechanisms underlying the accumulation of αSyn remain unknown but evidence is growing, that immune pathways and in particular colitis may play a critical role. Here we demonstrate that patients with inflammatory bowel disease (IBD) exhibit αSyn accumulation in their colon. We then confirmed in an experimental model of IBD that intestinal inflammation can trigger αSyn accumulation in the ENS of wildtype and αSyn transgenic mice. We discovered that the type and degree of inflammation modulates the extent of αSyn accumulation in the colon and that macrophage-related signaling limits this process. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain, including the substantia nigra, in 21-month but not 9-month-old αSyn transgenic mice. This was accompanied by loss of nigral tyrosine hydroxylase-immunoreactive neurons, another neuropathological hallmark of PD. Together, our data suggest a critical role for intestinal inflammation in the initiation and progression of PD.

Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology