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Published on: May 24, 2020
vCJD prion acquires altered virulence through trans-species infection
Masahiro Asano1, Shirou Mohri, James W Ironside
1Division of CJD Science and Technology, Department of Prion Research, Center for Translational and Advanced Animal Research on Human Diseases, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba, Sendai 980-8575, Japan.
Abstract:
Variant Creutzfeldt-Jakob disease (vCJD) appears to be caused by infection with the bovine spongiform encephalopathy (BSE) agent. To date, all patients with vCJD are homozygous for methionine at codon 129 of the PrP gene. To investigate the relationship between polymorphism at codon 129 and susceptibility to BSE or vCJD prions, we performed splenic follicular dendritic cell assay with humanized knock-in mice through peripheral infection. All humanized knock-in mice showed little or no susceptibility to BSE prions. Only the subset of humanized knock-in mice with codon 129 Met/Met genotype showed weak susceptibility by Western blotting. Surprisingly, we succeeded in the transmission of vCJD prions to humanized knock-in mice not only with codon 129 Met/Met but also with codon 129 Met/Val. Humanized knock-in mice with codon 129 Val/Val were not susceptible. The results suggest that human heterozygotes at codon 129 are also at risk for secondary infection with vCJD.
Insights
Variant Creutzfeldt-Jakob disease (vCJD) transmission was studied in mice with humanized PrP genes. Human heterozygotes at codon 129 may be susceptible to vCJD, indicating a risk for secondary infections.
Area of Science:
- Neuroscience
- Prion Diseases
- Genetics
Background:
- Variant Creutzfeldt-Jakob disease (vCJD) is linked to bovine spongiform encephalopathy (BSE) prions.
- All vCJD patients identified to date are homozygous for methionine at codon 129 of the PrP gene.
Purpose of the Study:
- To investigate the influence of codon 129 polymorphism on susceptibility to BSE and vCJD prions.
- To assess the risk of vCJD infection in individuals with different PrP genotypes.
Main Methods:
- Utilized humanized knock-in mice expressing human PrP transgenes.
- Infected mice peripherally and assessed prion susceptibility using splenic follicular dendritic cell assays and Western blotting.
Main Results:
- Humanized mice showed low susceptibility to BSE prions, with only Met/Met homozygotes exhibiting weak susceptibility.
- vCJD prions were transmitted to humanized mice with Met/Met and Met/Val genotypes.
- Mice with Val/Val genotype were not susceptible to vCJD prions.
Conclusions:
- Codon 129 polymorphism significantly impacts susceptibility to vCJD prions.
- Human heterozygotes (Met/Val) at codon 129 are susceptible to vCJD, suggesting a risk for secondary transmission.
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