eprintid: 10205268 rev_number: 7 eprint_status: archive userid: 699 dir: disk0/10/20/52/68 datestamp: 2025-02-26 08:12:09 lastmod: 2025-02-26 08:12:09 status_changed: 2025-02-26 08:12:09 type: article metadata_visibility: show sword_depositor: 699 creators_name: Zhang, Fuquan creators_name: Joiner, Susan creators_name: Linehan, Jacqueline M creators_name: Pintilii, Florin creators_name: Nazari, Tamsin creators_name: Argentina, Fabio creators_name: Preston, Connor creators_name: Taema, Maged creators_name: Cunningham, Thomas J creators_name: Asante, Emmanuel A creators_name: Mok, Tzehow creators_name: Mead, Simon creators_name: Brandner, Sebastian creators_name: Collinge, John creators_name: Wadsworth, Jonathan DF title: Isolation of a novel human prion strain from a PRNP codon 129 heterozygous vCJD patient ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: DF9 divisions: FA5 note: Copyright: © 2025 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. abstract: The epizootic prion disease of cattle, bovine spongiform encephalopathy (BSE), caused variant Creutzfeldt-Jakob disease (vCJD) in humans following dietary exposure. Codon 129 polymorphism of the human prion protein gene (PRNP), encoding either methionine (M) or valine (V), dictates the propagation of distinct human prion strains and up to now all but one neuropathologically confirmed vCJD patients have had a 129MM genotype. Concordant with this genetic association, transgenic modelling has established that human PrP 129V is incompatible with the vCJD prion strain and that depending on codon 129 genotype, primary human infection with BSE prions may, in addition to vCJD, result in sporadic CJD-like or novel phenotypes. In 2016 we saw the first neuropathologically confirmed case of vCJD in a patient with a codon 129MV genotype. This patient’s neuropathology and molecular strain type were pathognomonic of vCJD but their clinical presentation and neuroradiological features were more typical of sporadic CJD, suggestive of possible co-propagation of another prion strain. Here we report the transmission properties of prions from the brain and lymphoreticular tissues of the 129MV vCJD patient. Primary transmissions into transgenic mice expressing human PrP with different codon 129 genotypes mainly produced neuropathological and molecular phenotypes congruent to those observed in the same lines of mice challenged with prions from 129MM vCJD patient brain, indicative that the vCJD prion strain was the dominant propagating prion strain in the patient’s brain. Remarkably however, some transgenic mice challenged with 129MV vCJD patient brain propagated a novel prion strain type which at secondary passage was uniformly lethal in mice of all three PRNP codon 129 genotypes after similar short mean incubation periods. These findings establish that cattle BSE prions can trigger the co-propagation of distinct prion strains in humans. date: 2025-02-20 date_type: published publisher: Public Library of Science (PLoS) official_url: https://doi.org/10.1371/journal.ppat.1012904 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2364249 doi: 10.1371/journal.ppat.1012904 medium: Electronic-eCollection pii: PPATHOGENS-D-24-02288 lyricists_name: Mead, Simon lyricists_name: Wadsworth, Jonathan lyricists_name: Cunningham, Thomas lyricists_id: SMEAD68 lyricists_id: JWADS68 lyricists_id: TCUNN23 actors_name: Cunningham, Thomas actors_id: TCUNN23 actors_role: owner full_text_status: public publication: PLoS Pathogens volume: 21 number: 2 article_number: e1012904 event_location: United States issn: 1553-7366 editors_name: Bartz, Jason C citation: Zhang, Fuquan; Joiner, Susan; Linehan, Jacqueline M; Pintilii, Florin; Nazari, Tamsin; Argentina, Fabio; Preston, Connor; ... Wadsworth, Jonathan DF; + view all <#> Zhang, Fuquan; Joiner, Susan; Linehan, Jacqueline M; Pintilii, Florin; Nazari, Tamsin; Argentina, Fabio; Preston, Connor; Taema, Maged; Cunningham, Thomas J; Asante, Emmanuel A; Mok, Tzehow; Mead, Simon; Brandner, Sebastian; Collinge, John; Wadsworth, Jonathan DF; - view fewer <#> (2025) Isolation of a novel human prion strain from a PRNP codon 129 heterozygous vCJD patient. PLoS Pathogens , 21 (2) , Article e1012904. 10.1371/journal.ppat.1012904 <https://doi.org/10.1371/journal.ppat.1012904>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10205268/1/Isolation%20of%20a%20novel%20human%20prion%20strain%20from%20a%20PRNP%20codon%20129%20heterozygous%20vCJD%20patient.pdf