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

Enteric symptoms are hallmarks of prodromal Parkinson's disease (PD) that 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-syn32-46, binds with strong affinity to the HLA-DRB1∗15:01 allele implicated in autoimmune diseases. We report that α-syn32-46 immunization in a mouse expressing human HLA-DRB1∗15:01 triggers intestinal inflammation, leading to loss of enteric neurons, damaged enteric dopaminergic neurons, constipation, and weight loss. α-Syn32-46 immunization activates innate and adaptive immune gene signatures in the gut and induces changes in the CD4+ TH1/TH17 transcriptome that resemble tissue-resident memory (TRM) cells found in mucosal barriers during inflammation. Depletion of CD4+, but not CD8+, T cells partially rescues enteric neurodegeneration. Therefore, interaction of α-syn32-46 and HLA-DRB1∗15:0 is critical for gut inflammation and CD4+ T cell-mediated loss of enteric neurons in humanized mice, suggesting mechanisms that may underlie prodromal enteric PD.