271073 20240811004500.0 10.1172/JCI176344 doi pmid:39087478 pmid pmc:PMC11291267 pmc 0021-9738 ISSN 1558-8238 ISSN altmetric:165851406 altmetric DZNE-2024-00945 English 610 Mehra, Surabhi 0 Convergent generation of atypical prions in knockin mouse models of genetic prion disease. Ann Arbor, Mich. 2024 ASCJ article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1723110292_2209 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote Most cases of human prion disease arise due to spontaneous misfolding of WT or mutant prion protein, yet recapitulating this event in animal models has proven challenging. It remains unclear whether spontaneous prion generation can occur within the mouse lifespan in the absence of protein overexpression and how disease-causing mutations affect prion strain properties. To address these issues, we generated knockin mice that express the misfolding-prone bank vole prion protein (BVPrP). While mice expressing WT BVPrP (I109 variant) remained free from neurological disease, a subset of mice expressing BVPrP with mutations (D178N or E200K) causing genetic prion disease developed progressive neurological illness. Brains from spontaneously ill knockin mice contained prion disease-specific neuropathological changes as well as atypical protease-resistant BVPrP. Moreover, brain extracts from spontaneously ill D178N- or E200K-mutant BVPrP-knockin mice exhibited prion seeding activity and transmitted disease to mice expressing WT BVPrP. Surprisingly, the properties of the D178N- and E200K-mutant prions appeared identical before and after transmission, suggesting that both mutations guide the formation of a similar atypical prion strain. These findings imply that knockin mice expressing mutant BVPrP spontaneously develop a bona fide prion disease and that mutations causing prion diseases may share a uniform initial mechanism of action. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de Neurodegeneration Other Neuroscience Other Prions Other Prion Proteins NLM Chemicals Prions NLM Chemicals Animals MeSH Mice MeSH Prion Diseases: genetics MeSH Prion Diseases: pathology MeSH Prion Diseases: metabolism MeSH Gene Knock-In Techniques MeSH Disease Models, Animal MeSH Mice, Transgenic MeSH Prion Proteins: genetics MeSH Prion Proteins: metabolism MeSH Brain: metabolism MeSH Brain: pathology MeSH Mutation, Missense MeSH Humans MeSH Arvicolinae: genetics MeSH Arvicolinae: metabolism MeSH Amino Acid Substitution MeSH Prions: genetics MeSH Prions: metabolism MeSH Protein Folding MeSH Bourkas, Matthew Ec 1 Kaczmarczyk, Lech P:(DE-2719)2810486 2 Stuart, Erica 3 Arshad, Hamza 4 Griffin, Jennifer K 5 Frost, Kathy L 6 Walsh, Daniel J 7 Supattapone, Surachai 8 Booth, Stephanie A 9 Jackson, Walker Scot P:(DE-2719)2810253 10 Watts, Joel C 11 10.1172/JCI176344 Vol. 134, no. 15, p. e176344 PERI:(DE-600)2018375-6 15 e176344 The journal of clinical investigation 134 2024 0021-9738 OpenAccess http://pub.dzne.de/record/271073/files/DZNE-2024-00945.pdf OpenAccess pdfa http://pub.dzne.de/record/271073/files/DZNE-2024-00945.pdf?subformat=pdfa oai:pub.dzne.de:271073 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 2 P:(DE-2719)2810486 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 10 P:(DE-2719)2810253 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-352 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Mechanisms 0 2024 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2023-10-22 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2023-10-22 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2023-10-22 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2023-10-22 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search 2023-10-22 IF >= 15 StatID:(DE-HGF)9915 StatID J CLIN INVEST : 2022 2023-10-22 JCR StatID:(DE-HGF)0100 StatID J CLIN INVEST : 2022 2023-10-22 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2023-10-22 DBCoverage StatID:(DE-HGF)0501 StatID DOAJ Seal 2023-02-14T21:03:14Z DBCoverage StatID:(DE-HGF)0500 StatID DOAJ 2023-02-14T21:03:14Z WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2023-10-22 Fees StatID:(DE-HGF)0700 StatID 2023-10-22 OpenAccess StatID:(DE-HGF)0510 StatID Creative Commons Attribution CC BY 4.0 LIC:(DE-HGF)CCBY4 HGFVOC Peer Review StatID:(DE-HGF)0030 StatID ASC 2023-10-22 Article Processing Charges StatID:(DE-HGF)0561 StatID 2023-10-22 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2023-10-22 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2023-10-22 DBCoverage StatID:(DE-HGF)0320 StatID PubMed Central 2023-10-22 DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2023-10-22 Peer Review StatID:(DE-HGF)0030 StatID DOAJ : Peer review 2023-02-14T21:03:14Z I:(DE-2719)1013019 AG Jackson Selective Vulnerability of Neurodegenerative Diseases 0 journal VDB UNRESTRICTED I:(DE-2719)1013019 FullTexts