{"doi":"10.1016/j.jbc.2024.108062","title":"Chaperone-mediated disaggregation of infectious prions releases particles that seed new prion formation in a strain-specific manner","abstract":"The mammalian prion protein can form infectious, nonnative, and protease resistant aggregates (PrP D ), which cause lethal prion diseases like human Creutzfeldt-Jakob disease. PrP D seeds the formation of new infectious prions by interacting with and triggering the refolding of the normally soluble mammalian prion protein, PrP C , into more PrP D . Refolding of misfolded proteins in the cell is carried out by molecular chaperones such as Grp78. We have recently shown that Grp78 sensitizes PrP D to proteases, indicating structural alterations and leading to its degradation. However, the process of chaperone-mediated PrP D disaggregation, the chaperones involved, and the effect of disaggregation on PrP D seeding activity are unclear. We have now monitored the structural modification, disaggregation, and seeding activity of PrP D from two mouse adapted prion strains, 22L and 87V, in the presence of Grp78 and two forms of the Hsp110 disaggregase chaperone family, Hsp105 and Apg-2. We found that both forms of Hsp110 induced similar amounts of disaggregation and structural change in the protease resistant cores of PrP D from both strains. However, 22L PrP D was more susceptible to destabilization and disaggregation by the chaperones than 87V. Surprisingly, despite disaggregation of both strains, only the 22L PrP D aggregates released by the chaperones had seeding activity, with both forms of Hsp110 enhancing the Grp78 mediated release of these aggregates. Our data show that disassembly of PrP D by Grp78 and Hsp110 chaperones can release seeding particles of PrP D in a strain-specific manner, potentially facilitating prion replication and spread.","journal":"Journal of Biological Chemistry","year":2024,"id":458933,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9497,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":303819,"name":"Suzette A. Priola","orcid":"0000-0003-0303-3951","position":1,"is_corresponding":false},{"id":768603,"name":"Daniel Shoup","orcid":null,"position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T02:03:50.608887Z","pmid":"39662829","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":[]}