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Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease

Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several c...

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Autores principales: Friedman-Levi, Yael, Meiner, Zeev, Canello, Tamar, Frid, Kati, Kovacs, Gabor G., Budka, Herbert, Avrahami, Dana, Gabizon, Ruth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3207931/
https://www.ncbi.nlm.nih.gov/pubmed/22072968
http://dx.doi.org/10.1371/journal.ppat.1002350
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author Friedman-Levi, Yael
Meiner, Zeev
Canello, Tamar
Frid, Kati
Kovacs, Gabor G.
Budka, Herbert
Avrahami, Dana
Gabizon, Ruth
author_facet Friedman-Levi, Yael
Meiner, Zeev
Canello, Tamar
Frid, Kati
Kovacs, Gabor G.
Budka, Herbert
Avrahami, Dana
Gabizon, Ruth
author_sort Friedman-Levi, Yael
collection PubMed
description Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M) E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5–6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments.
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spelling pubmed-32079312011-11-09 Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease Friedman-Levi, Yael Meiner, Zeev Canello, Tamar Frid, Kati Kovacs, Gabor G. Budka, Herbert Avrahami, Dana Gabizon, Ruth PLoS Pathog Research Article Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M) E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5–6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments. Public Library of Science 2011-11-03 /pmc/articles/PMC3207931/ /pubmed/22072968 http://dx.doi.org/10.1371/journal.ppat.1002350 Text en Friedman-Levi et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Friedman-Levi, Yael
Meiner, Zeev
Canello, Tamar
Frid, Kati
Kovacs, Gabor G.
Budka, Herbert
Avrahami, Dana
Gabizon, Ruth
Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease
title Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease
title_full Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease
title_fullStr Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease
title_full_unstemmed Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease
title_short Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease
title_sort fatal prion disease in a mouse model of genetic e200k creutzfeldt-jakob disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3207931/
https://www.ncbi.nlm.nih.gov/pubmed/22072968
http://dx.doi.org/10.1371/journal.ppat.1002350
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