{"doi":"10.1101/2022.02.03.479014","title":"Interaction of an α-synuclein epitope with HLA-DRB1*15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":299777,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9505,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":708583,"name":"Connor Monahan","orcid":"0000-0003-3245-6187","position":1,"is_corresponding":false},{"id":990429,"name":"Nicholas Sloan","orcid":null,"position":2,"is_corresponding":false},{"id":990430,"name":"Jamie Bergen","orcid":null,"position":3,"is_corresponding":false},{"id":906078,"name":"Sanjid Shahriar","orcid":"0000-0003-4911-9742","position":4,"is_corresponding":false},{"id":990077,"name":"Seon Woo Kim","orcid":"0000-0002-5774-0224","position":5,"is_corresponding":false},{"id":55670,"name":"Alessandro Sette","orcid":"0000-0001-7013-2250","position":6,"is_corresponding":false},{"id":906634,"name":"Tyler Cutforth","orcid":null,"position":7,"is_corresponding":false},{"id":990078,"name":"Ellen Kanter","orcid":"0000-0002-7475-5006","position":8,"is_corresponding":false},{"id":272299,"name":"Dritan Agalliu","orcid":"0000-0002-1365-6450","position":9,"is_corresponding":false},{"id":230247,"name":"David Sulzer","orcid":"0000-0001-7632-0439","position":10,"is_corresponding":false},{"id":864497,"name":"Francesca Garretti","orcid":"0000-0002-6609-8034","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T00:31:49.412501Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}