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Abbreviated incubation times for human prions in mice expressing a chimeric mouse-human prion protein transgene.

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.

SUBMITTER: Korth C

PROVIDER: S-EPMC153633 | biostudies-literature | 2003 Apr

REPOSITORIES: biostudies-literature

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Abbreviated incubation times for human prions in mice expressing a chimeric mouse-human prion protein transgene.

Korth Carsten C Kaneko Kiyotoshi K Groth Darlene D Heye Norbert N Telling Glenn G Mastrianni James J Parchi Piero P Gambetti Pierluigi P Will Robert R Ironside James J Heinrich Cornelia C Tremblay Patrick P DeArmond Stephen J SJ Prusiner Stanley B SB

Proceedings of the National Academy of Sciences of the United States of America 20030408 8

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 ...[more]

PMID: 12684540

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Project description:BackgroundTransmissible Spongiform Encephalopathies (TSEs) are a group of progressive fatal neurodegenerative disorders, triggered by abnormal folding of the endogenous prion protein molecule. The encoding gene is a major biological factor influencing the length of the asymptomatic period after infection. It remains unclear the extent to which the variation between quantitative trait loci (QTLs) reported in mouse models is due to methodological differences between approaches or genuine differences between traits. With this in mind, our approach to identifying genetic factors has sought to extend the linkage mapping approach traditionally applied, to a series of additional traits, while minimising methodological variability between them. Our approach allows estimations of heritability to be derived, as well as predictions to be made about possible existence of genetic overlap between the various traits.Methodology/principal findingsOur data indicate a surprising degree of heritability (up to 60%). Correlations between traits are also identified. A series of QTLs on chromosomes 1, 2, 3, 4, 6, 11 and 18 accompany our heritability estimates. However, only a locus on chromosome 11 has a general effect across all 4 models explored.Conclusions/significanceWe have achieved some success in detecting novel and pre-existing QTLs associated with incubation time. However, aside from the general effects described, the model-specific nature of the broader host genetic architecture has also been brought into clearer focus. This suggests that genetic overlap can only partially account for the general heritability of incubation time when factors, such as the nature of the TSE agent and the route of administration are considered. This point is highly relevant to vCJD (a potential threat to public health) where the route of primary importance is oral, while the QTLs being sought derive exclusively from studies of the ic route. Our results highlight the limitations of a single-model approach to QTL-mapping of TSEs.

Dataset Information

Abbreviated incubation times for human prions in mice expressing a chimeric mouse-human prion protein transgene.

Publications

Abbreviated incubation times for human prions in mice expressing a chimeric mouse-human prion protein transgene.

Similar Datasets

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