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bioRxiv · 10.1101/2022.02.03.479014

Interaction of an α-synuclein epitope with HLA-DRB1*15:01 initiates early enteric features of Parkinson's disease in humanized mice

Garretti, F.·Monahan, C.·Sloan, N.·Shariar, S.·Kim, S. W.·Sette, A.·Cutforth, T.·Kanter, E.·Sulzer, D.·Agalliu, D.
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Abstract

Enteric symptoms, including constipation, are hallmarks of prodromal Parkinsons disease (PD) that can appear decades before the onset of motor symptoms and diagnosis. PD patients possess circulating T cells that recognize specific -synuclein-(-syn)-derived epitopes. One epitope, -syn32-46, binds with strong affinity to the HLA-DRB1*15:01 allele implicated in autoimmune diseases. We report that -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. -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 -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. HIGHLIGHTS AND eTOC BlurbO_LI-syn32-46 immunization of an HLA-DRB1*15:01 mouse triggers weight loss and constipation. C_LIO_LI-syn32-46 immunizations induce gut inflammation, loss of enteric neurons and damage to dopaminergic neurons. C_LIO_LI-syn32-46 immunization induces innate and adaptive immune responses in the gut. C_LIO_LIDepletion of CD4+, but not CD8+, T cells partially rescues enteric neural loss. C_LIO_LIAn interaction between -syn32-46 and HLA-DRB1*15:01 is critical for this model of prodromal PD. C_LI Parkinsons disease (PD) patients exhibit elevated number of circulating T cells that recognize -synuclein-(-syn)- epitopes, particularly during early disease stages. One epitope, -syn32-46, interacts with the HLA-DRB1*15:01; however, its role in PD pathogenesis remains unknown. Garretti et al. show that -syn32-46 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 -syn autoimmunity in HLA-DRB1*15:01 carriers in prodromal PD.

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Garretti, F., Monahan, C., Sloan, N., Shariar, S., Kim, S. W., Sette, A., Cutforth, T., Kanter, E., Sulzer, D., Agalliu, D.. 2022-02-05. Interaction of an α-synuclein epitope with HLA-DRB1*15:01 initiates early enteric features of Parkinson's disease in humanized mice. https://doi.org/10.1101/2022.02.03.479014

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