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

Francesca Garretti; Connor Monahan; Nicholas Sloan; Sanjid Shariar; Seon Woo Kim; Alessandro Sette; Tyler Cutforth; Ellen Kanter; Dritan Agalliu; David Sulzer

doi:10.1101/2022.02.03.479014

SUMMARY

Parkinson’s disease (PD) patients possess circulating T cells that recognize specific α-synuclein-(α-syn)-derived epitopes. One epitope, α-syn_32-46, interacts strongly with the HLA-DRB1*15:01 allele implicated in multiple autoimmune diseases. Whether this interaction and α-syn-specific T cells play roles in PD pathogenesis remains unknown. We report that α-syn_32-46 immunization of a humanized mouse that expresses HLA-DRB1*15:01 triggers intestinal inflammation. This enteric pathology is characterized by activation of innate and adaptive immune responses and type I interferon signaling as well as loss of enteric dopaminergic neurons in the submucosal plexus, and results in constipation and weight loss. Depletion of CD4⁺, but not CD8⁺, T cells partially rescues enteric neurodegeneration. Thus, an interaction between α-syn_32-46 and HLA-DRB1*15:01 induces gut inflammation and CD4⁺ T cell-mediated loss of enteric dopaminergic neurons in the humanized mice. These findings suggest a mechanism for the prodromal enteric features of PD and indicate future directions for disease screening and treatment.

HIGHLIGHTS AND eTOC Blurb

α-syn_32-46 immunization of a HLA-DRB1*15:01 mouse triggers weight loss and constipation.
α-syn_32-46 immunizations induce gut inflammation and loss of enteric dopaminergic neurons.
Depletion of CD4⁺, but not CD8⁺, T cells partially rescues enteric neurodegeneration.
Interaction between α-syn_32-46 and HLA-DRB1*15:01 are critical for the prodromal phase of PD.

HIGHLIGHTS AND eTOC BlurbParkinson’s disease (PD) patients have circulating T cells that recognize α-synuclein-(α-syn)-epitopes. 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 humanized mouse expressing HLA-DRB1*15:01 triggers intestinal inflammation, loss of enteric dopaminergic neurons, constipation and weight loss, suggesting a critical role in the prodromal PD.

Competing Interest Statement

The authors have declared no competing interest.

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