{"doi":"10.1371/journal.ppat.1010956","title":"The E46K mutation modulates α-synuclein prion replication in transgenic mice","abstract":"In multiple system atrophy (MSA), the α-synuclein protein misfolds into a self-templating prion conformation that spreads throughout the brain, leading to progressive neurodegeneration. While the E46K mutation in α-synuclein causes familial Parkinson's disease (PD), we previously discovered that this mutation blocks in vitro propagation of MSA prions. Recent studies by others indicate that α-synuclein adopts a misfolded conformation in MSA in which a Greek key motif is stabilized by an intramolecular salt bridge between residues E46 and K80. Hypothesizing that the E46K mutation impedes salt bridge formation and, therefore, exerts a selective pressure that can modulate α-synuclein strain propagation, we asked whether three distinct α-synuclein prion strains could propagate in TgM47+/- mice, which express human α-synuclein with the E46K mutation. Following intracranial injection of these strains, TgM47+/- mice were resistant to MSA prion transmission, whereas recombinant E46K preformed fibrils (PFFs) transmitted neurological disease to mice and induced the formation of phosphorylated α-synuclein neuropathology. In contrast, heterotypic seeding following wild-type (WT) PFF-inoculation resulted in preclinical α-synuclein prion propagation. Moreover, when we inoculated TgM20+/- mice, which express WT human α-synuclein, with E46K PFFs, we observed delayed transmission kinetics with an incomplete attack rate. These findings suggest that the E46K mutation constrains the number of α-synuclein prion conformations that can propagate in TgM47+/- mice, expanding our understanding of the selective pressures that impact α-synuclein prion replication.","journal":"PLoS Pathogens","year":2022,"id":260475,"datarank":0.42498200160843247,"base_score":2.833213344056216,"endowment":2.833213344056216,"self_citation_contribution":0.42498200160843247,"citation_network_contribution":0.0,"self_endowment_contribution":0.42498200160843247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"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":422776,"name":"Jisoo Lee","orcid":"0000-0001-6279-7025","position":1,"is_corresponding":false},{"id":472298,"name":"Abby Oehler","orcid":null,"position":2,"is_corresponding":false},{"id":914705,"name":"Lyn Batia","orcid":null,"position":3,"is_corresponding":false},{"id":914706,"name":"Aryanna Wiggins-Gamble","orcid":null,"position":4,"is_corresponding":false},{"id":914707,"name":"Jeffrey Lau","orcid":null,"position":5,"is_corresponding":false},{"id":328423,"name":"Felicia K. Ooi","orcid":"0000-0003-4766-2477","position":6,"is_corresponding":false},{"id":108129,"name":"Gregory E. Merz","orcid":"0000-0003-0842-4935","position":7,"is_corresponding":false},{"id":914183,"name":"Man Wang","orcid":"0000-0002-7364-7994","position":8,"is_corresponding":false},{"id":347215,"name":"Daniel A. Mordes","orcid":"0000-0002-4805-7394","position":9,"is_corresponding":false},{"id":403981,"name":"Steven H. Olson","orcid":"0000-0001-9615-9355","position":10,"is_corresponding":false},{"id":471322,"name":"Amanda L. Woerman","orcid":"0000-0003-4029-1968","position":11,"is_corresponding":false},{"id":914182,"name":"Sara A. M. Holec","orcid":"0000-0003-0800-1115","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:26:07.666421Z","pmid":"36454879","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":[]}