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Interaction of an α-synuclein epitope with HLA-DRB1*15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease
Published June 12, 2023
Output Details
Preprint March 17, 2022
Published June 12, 2023
Description
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-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 HLA-DRB1*15:01 triggers intestinal inflammation leading to loss of enteric neurons, damage of 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 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-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 potential mechanisms of prodromal enteric PD.
Identifier (DOI)
10.1016/j.neuron.2023.07.015