A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity

Background: Alpha-synuclein (aS) is a nerve cell protein associated with Parkinson disease (PD). Accumulation of aS within the enteric nervous system (ENS) and its traffic from the gut to the brain are implicated in the pathogenesis and progression of PD. aS has no known function in humans and the reason for its accumulation within the ENS is unknown. Several recent studies conducted in rodents have linked aS to immune cell activation in the central nervous system. We hypothesized that aS in the ENS might play a role in the innate immune defenses of the human gastrointestinal (GI) tract. Methods: We immunostained endoscopic biopsies for aS from children with documented gastric and duodenal tracted norovirus. To determine whether aS exhibited immune-modulatory activity, we examined whether human aS induced leukocyte migration and dendritic cell maturation. Findings: We showed that the expression of aS in the enteric neurites of the upper GI tract of pediatric patients positively correlated with the degree of acute and chronic inflammation in the intestinal wall. In intestinal allograft subjects who were closely monitored for infection, expression of aS was induced during norovirus infection. We also demonstrated that both monomeric and oligomeric aS have potent chemoattractant activity, causing the migration of neutrophils and monocytes dependent on the presence of the integrin subunit, CD11b, and that both forms of aS stimulate dendritic cell maturation. Interpretation: These findings strongly suggest that aS is expressed within the human ENS to direct intestinal inflammation and implicates common GI infections in the pathogenesis of PD. (C) 2017 S. Karger AG, Basel