Prion potentiation after life-long dormancy in mice devoid of PrP
| Autor: | Mohammed Moudjou, Fabienne Reine, Davy Martin, Armand Perret-Liaudet, Isabelle Quadrio, Christel Michel, Olivier Andreoletti, Human Rezaei, Naima Aron, Guillaume Fichet, Laetitia Herzog, Vincent Béringue, Angélique Igel-Egalon |
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| Přispěvatelé: | Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation pour la Recherche Medicale (Equipe FRM DEQ20150331689), Agence Nationale de Securite du Medicament et des Produits de Sante (2014S033 HAP ANSM 2014/iPDB), RIOU, Christine, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Transgene animal diseases [SDV]Life Sciences [q-bio] prion disease clearance Biology transgenic mice 03 medical and health sciences 0302 clinical medicine Bioassay Infectivity AcademicSubjects/SCI01870 General Engineering Long-term potentiation Biological activity Virology 3. Good health nervous system diseases [SDV] Life Sciences [q-bio] 030104 developmental biology misfolded assemblies Dormancy Original Article AcademicSubjects/MED00310 CNS 030217 neurology & neurosurgery Clearance |
| Zdroj: | Brain Communications Brain Communications, Oxford University Press on behalf of the Guarantors of Brain, 2021, 3 (2), ⟨10.1093/braincomms/fcab092⟩ Brain Communications, 2021, 3 (2), ⟨10.1093/braincomms/fcab092⟩ |
| ISSN: | 2632-1297 |
| DOI: | 10.1093/braincomms/fcab092⟩ |
| Popis: | Prions are neurotropic pathogens composed of misfolded assemblies of the host-encoded prion protein PrPC which replicate by recruitment and conversion of further PrPC by an autocatalytic seeding polymerization process. 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–Jakob 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. Abbreviated summary Martin et al. report lifelong persistence of sporadic Creutzfeldt–Jakob disease prions in the brain of mice lacking the endogenous prion protein gene and disease potentiation—without strain evolution—on retrotransmission to humanized mice. These findings highlight the risk of indefinite prion persistence with therapeutic strategies lowering the prion protein. Graphical Abstract Graphical Abstract |
| Databáze: | OpenAIRE |
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