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

PLoS Pathogens

Ruth Gabizon¹  Yael Friedman-Levi¹  Zeev Meiner¹  Dana Avrahami¹  Tamar Canello¹  Kati Frid¹  Herbert Budka²  Gabor G. Kovacs² 

[1] Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Jerusalem, Israel;Institute of Neurology, Medical University Vienna, Austria

关键词: Mouse models;    Prion diseases;    Brain diseases;    Genetics of disease;    Human genetics;    Insertion mutation;    Infectious disease control;    Limbs (anatomy);   

DOI  :  10.1371/journal.ppat.1002350

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY