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While it has long been shown that mouse-adapted prions cannot replicate and are rapidly cleared in transgenic PrP0\/0 mice invalidated for PrPC, these experiments have not been done with other prions, including from natural resources, and more sensitive methods to detect prion biological activity. Using transgenic mice expressing human PrP to bioassay prion infectivity and RT-QuIC cell-free assay to measure prion seeding activity, we report that prions responsible for the most prevalent form of sporadic Creutzfeldt\u2013Jakob disease in human (MM1-sCJD) can persist indefinitely in the brain of intra-cerebrally inoculated PrP0\/0 mice. While low levels of seeding activity were measured by RT-QuIC in the brain of the challenged PrP0\/0 mice, the bio-indicator humanized mice succumbed at a high attack rate, suggesting relatively high levels of persistent infectivity. Remarkably, these humanized mice succumbed with delayed kinetics as compared to MM1-sCJD prions directly inoculated at low doses, including the limiting one. Yet, the disease that did occur in the humanized mice on primary and subsequent back-passage from PrP0\/0 mice shared the neuropathological and molecular characteristics of MM1-sCJD prions, suggesting no apparent strain evolution during lifelong dormancy in PrP0\/0 brain. Thus, MM1-sCJD prions can persist for the entire life in PrP0\/0 brain with potential disease potentiation on retrotransmission to susceptible hosts. These findings highlight the capacity of prions to persist and rejuvenate in non-replicative environments, interrogate on the type of prion assemblies at work and alert on the risk of indefinite prion persistence with PrP-lowering therapeutic strategies.<\/jats:p>","DOI":"10.1093\/braincomms\/fcab092","type":"journal-article","created":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T03:49:30Z","timestamp":1619149770000},"source":"Crossref","is-referenced-by-count":17,"title":["Prion potentiation after life-long dormancy in mice devoid of PrP"],"prefix":"10.1093","volume":"3","author":[{"given":"Davy","family":"Martin","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, INRAE, UVSQ, VIM, 78 350 Jouy-en-Josas, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabienne","family":"Reine","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, INRAE, UVSQ, VIM, 78 350 Jouy-en-Josas, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laetitia","family":"Herzog","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, INRAE, UVSQ, VIM, 78 350 Jouy-en-Josas, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang\u00e9lique","family":"Igel-Egalon","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, INRAE, UVSQ, VIM, 78 350 Jouy-en-Josas, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naima","family":"Aron","sequence":"additional","affiliation":[{"name":"INRAE, \u00c9cole Nationale V\u00e9t\u00e9rinaire de Toulouse, IHAP, 31 000 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christel","family":"Michel","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, INRAE, UVSQ, VIM, 78 350 Jouy-en-Josas, 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armand","family":"Perret-Liaudet","sequence":"additional","affiliation":[{"name":"Neurobiology Laboratory, Biochemistry and Molecular Biology Department, H\u00f4pitaux de Lyon, 69 000 Lyon, France"},{"name":"University of Lyon 1, CNRS UMR5292, INSERM U1028, BioRan, 69 000 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Andr\u00e9oletti","sequence":"additional","affiliation":[{"name":"INRAE, \u00c9cole Nationale V\u00e9t\u00e9rinaire de Toulouse, IHAP, 31 000 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Human","family":"Rezaei","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, INRAE, UVSQ, VIM, 78 350 Jouy-en-Josas, 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