Interaction of an α-synuclein epitope with HLA-DRB1*15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease

SUMMARY Enteric symptoms, including constipation, are hallmarks of prodromal Parkinson’s disease (PD) that can appear decades before the onset of motor symptoms and diagnosis. PD patients possess circulating T cells that recognize specific α-synuclein-(α-syn)-derived epitopes. One epitope, α-syn 32-46 , binds with strong affinity to the HLA-DRB1*15:01 allele implicated in autoimmune diseases. We report that α-syn 32-46 immunization in a mouse expressing HLA-DRB1*15:01 triggers intestinal inflammation leading to loss of enteric neurons, damage of enteric dopaminergic neurons, constipation and weight loss. α-Syn 32-46 immunization activates innate and adaptive immune gene signatures in the gut and induces changes in CD4 + TH1/ TH17 transcriptome that resemble tissue resident memory cells found in mucosal barriers during inflammation. Depletion of CD4 + , but not CD8 + , T cells partially rescues enteric neurodegeneration. Therefore, interaction of α-syn 32-46 and HLA-DRB1*15:0 is critical for gut inflammation and CD4 + T cell-mediated loss of enteric neurons in humanized mice, suggesting potential mechanisms of prodromal enteric PD. HIGHLIGHTS AND eTOC Blurb α-syn 32-46 immunization of an HLA-DRB1*15:01 mouse triggers weight loss and constipation. α-syn 32-46 immunizations induce gut inflammation, loss of enteric neurons and damage to dopaminergic neurons. α-syn 32-46 immunization induces innate and adaptive immune responses in the gut. Depletion of CD4 + , but not CD8 + , T cells partially rescues enteric neural loss. An interaction between α-syn 32-46 and HLA-DRB1*15:01 is critical for this model of prodromal PD. Parkinson’s disease (PD) patients exhibit elevated number of circulating T cells that recognize α-synuclein-(α-syn)- epitopes, particularly during early disease stages. One epitope, α-syn 32-46 , interacts with the HLA-DRB1*15:01; however, its role in PD pathogenesis remains unknown. Garretti et al . show that α-syn 32-46 immunization of a mouse expressing HLA-DRB1*15:01 triggers intestinal inflammation, a loss of enteric neurons, constipation and weight loss, suggesting a critical role for α-syn autoimmunity in HLA-DRB1*15:01 carriers in prodromal PD.