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Humanized knock-in mice expressing chimeric prion protein showed varied susceptibility to different human prions

Yuzuru Taguchi1, Shirou Mohri, James W Ironside

  • 1Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai, Japan.

The American Journal of Pathology
|November 25, 2003
PubMed

Insights

A new knock-in mouse model (Ki-ChM) shows varied susceptibility to human prions, offering a valuable tool for prion disease research and diagnostics. This model aids in understanding prion transmission and developing faster diagnostic methods.

Area of Science:

  • Neuroscience
  • Prion Biology
  • Genetics

Background:

  • Human prion diseases, such as Creutzfeldt-Jakob disease (CJD), pose significant research and diagnostic challenges.
  • Developing animal models that efficiently mimic human prion diseases is crucial for understanding pathogenesis and developing therapies.
  • Previous transgenic mouse models have shown limitations in susceptibility to diverse human prion strains.

Purpose of the Study:

  • To evaluate the susceptibility profile of a novel knock-in mouse model (Ki-ChM) expressing a human-mouse chimeric prion protein (PrP) to various human prion strains.
  • To assess the utility of the Ki-ChM mouse as a research and diagnostic tool for human prion diseases.
  • To compare the Ki-ChM mouse's susceptibility with existing transgenic models.

Main Methods:

  • Generation of a knock-in mouse line (Ki-ChM) expressing a chimeric human-mouse PrP.
  • Intracerebral inoculation of various human prion strains, including sporadic CJD (MM1, MV1, MM2, VV2), familial CJD (M232R), variant CJD, and dura graft-associated CJD (dCJD) with and without amyloid plaques.
  • Monitoring of disease onset, incubation periods, and clinical signs in inoculated mice.
  • Comparison of susceptibility profiles across different prion types and with other transgenic models.

Main Results:

  • The Ki-ChM mice exhibited differential susceptibility to human prions.
  • High susceptibility was observed for MM1 and MV1 sporadic CJD, familial CJD (M232R), and dCJD without amyloid plaques, with short incubation periods (approx. 150 days).
  • Lower susceptibility was noted for MM2 sporadic CJD and variant CJD, with some mice showing no transmission.
  • Complete resistance was observed against VV2 sporadic CJD and dCJD with amyloid plaques.

Conclusions:

  • The Ki-ChM mouse model demonstrates a distinct susceptibility profile to human prions, making it a valuable tool for prion disease research.
  • The model's ability to develop disease within a relatively short incubation period offers new avenues for developing rapid diagnostic tools.
  • Further development of genetically engineered mice, like the Ki-ChM model, holds promise for advancing our understanding and management of human prion diseases.

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