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Updated: Sep 26, 2026
Protein Misfolding Cyclic Amplification of Prions
Published on: November 7, 2012
Abbreviated incubation times for human prions in mice expressing a chimeric mouse-human prion protein transgene
Carsten Korth1, Kiyotoshi Kaneko, Darlene Groth
1Institute for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, CA 94143, USA.
Abstract:
Transgenic (Tg) mouse lines that express chimeric mouse-human prion protein (PrP), designated MHu2M, are susceptible to prions from patients with sporadic Creutzfeldt-Jakob disease (sCJD). With the aim of decreasing the incubation time to fewer than 200 days, we constructed transgenes in which one or more of the nine human residues in MHu2M were changed to mouse. The construct with murine residues at positions 165 and 167 was expressed in Tg(MHu2M,M165V,E167Q) mice and resulted in shortening the incubation time to approximately 110 days for prions from sCJD patients. The construct with a murine residue at position 96 resulted in lengthening the incubation time to more than 280 days for sCJD prions. When murine residues 96, 165, and 167 were expressed, the abbreviated incubation times for sCJD prions were abolished. Variant CJD prions showed prolonged incubation times between 300 and 700 days in Tg(MHu2M) mice on first passage and incubation times of approximately 350 days in Tg(MHu2M,M165V,E167Q) mice. On second and third passages of variant CJD prions in Tg(MHu2M) mice, multiple strains of prions were detected based on incubation times and the sizes of the protease-resistant, deglycosylated PrP(Sc) fragments. Our discovery of a previously undescribed chimeric transgene with abbreviated incubation times for sCJD prions should facilitate studies on the prion species barrier and human prion diversity.
Insights
Researchers modified mouse-human prion protein (PrP) transgenes to shorten incubation times for sporadic Creutzfeldt-Jakob disease (sCJD) prions. Specific mutations significantly reduced incubation periods, aiding prion disease research.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Transgenic (Tg) mouse models expressing chimeric mouse-human prion protein (PrP) are susceptible to sporadic Creutzfeldt-Jakob disease (sCJD) prions.
- Understanding prion strain diversity and species barrier is crucial for prion disease research.
Purpose of the Study:
- To engineer mouse-human PrP transgenes with modified residues to shorten incubation times for sCJD prions.
- To investigate the impact of specific residue changes on prion disease incubation periods and strain characteristics.
Main Methods:
- Construction and expression of modified chimeric mouse-human PrP transgenes in Tg mice.
- Inoculation of Tg mice with sCJD and variant CJD prions.
- Monitoring and recording of incubation times and analysis of PrP(Sc) fragments.
Main Results:
- A Tg mouse line (Tg(MHu2M,M165V,E167Q)) expressing chimeric PrP with murine residues at positions 165 and 167 showed shortened incubation times (~110 days) for sCJD prions.
- A murine residue at position 96 lengthened sCJD prion incubation time (>280 days), while combined mutations at 96, 165, and 167 abolished this shortening.
- Variant CJD prions exhibited prolonged incubation times in Tg(MHu2M) and modified Tg mice, with evidence of multiple strains upon serial passage.
Conclusions:
- The engineered chimeric transgene Tg(MHu2M,M165V,E167Q) significantly abbreviates incubation times for sCJD prions.
- Specific PrP residue modifications influence prion incubation periods and can reveal prion strain diversity.
- These findings provide valuable tools for studying the prion species barrier and human prion diseases.
