{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:53:59Z","timestamp":1790891639835,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014536","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000}}],"reference-count":116,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-169048"],"award-info":[{"award-number":["PJT-169048"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Canadian Foundation for Innovation"},{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs Program","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Prions are misfolded, self-propagating versions of cellular proteins. In humans and animals, misfolding of the cellular prion protein (PrP\n                    <jats:sup>C<\/jats:sup>\n                    ) causes invariably fatal transmissible neurodegenerative diseases. Little is known about how mammalian prions replicate in the brain, including whether other proteins participate in prion replication\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Several members of the protein disulfide isomerase family have been shown to reside in close spatial proximity to PrP\n                    <jats:sup>C<\/jats:sup>\n                    in cells and mice, implying that they could be involved in prion biogenesis. Here, we show that stable knock-down of the protein disulfide isomerase P4HB (also called PDIA1) in prion-susceptible CAD5 cells reduces PrP\n                    <jats:sup>C<\/jats:sup>\n                    levels and hinders the generation of protease-resistant PrP (PrP\n                    <jats:sup>res<\/jats:sup>\n                    ) following infection with two different prion strains. Moreover, transient knock-down of P4HB decreases PrP\n                    <jats:sup>res<\/jats:sup>\n                    levels in cells with established prion infection. Partial reduction of P4HB activity using the P4HB-selective inhibitor KSC-34 also decreases PrP\n                    <jats:sup>C<\/jats:sup>\n                    levels in uninfected CAD5 cells whereas treatment of prion-infected CAD5 cells with KSC-34 results in higher levels of PrP\n                    <jats:sup>res<\/jats:sup>\n                    . A proportion of P4HB reaches the cell surface where PrP\n                    <jats:sup>C<\/jats:sup>\n                    is located, and a secreted P4HB variant increases PrP\n                    <jats:sup>res<\/jats:sup>\n                    levels in cells. Collectively, these results suggest that P4HB influences PrP\n                    <jats:sup>C<\/jats:sup>\n                    homeostasis and modulates the conversion of PrP\n                    <jats:sup>C<\/jats:sup>\n                    into misfolded species. Thus, targeting P4HB during prion disease may have therapeutic benefit.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014536","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:35:43Z","timestamp":1787074543000},"page":"e1014536","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["The protein disulfide isomerase P4HB\/PDIA1 modulates cellular and misfolded forms of the prion protein"],"prefix":"10.1371","volume":"22","author":[{"given":"Genki","family":"Amano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamza","family":"Arshad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeel","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerold","family":"Schmitt-Ulms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2604-2925","authenticated-orcid":true,"given":"Joel 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