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High Prion and PrPSc Levels but Delayed Onset of Disease in Scrapie-Inoculated Mice Heterozygous for a Disrupted PrP Gene

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Abstract

Background

It has been proposed that the prion, the infectious agent of transmissible spongiform encephalopathies, is PrPSc, a post-translationally modified form of the normal host protein PrPC. We showed previously that mice devoid of PrPC (Prn-p0/0) are completely resistant to scrapie. We now report on the unexpected response of heterozygous (Prn-p0/+) mice to scrapie infection.

Materials and Methods

Prn-p0/+, Prn-p0/0 and Prn-p+/+ mice were obtained from crosses of Prn-p0/+ mice. Mice were inoculated intracerebrally with mouse-adapted scrapie agent and the clinical progression of the disease recorded. Mice were sacrificed at intervals, PrPSc was determined as protease-resistant PrP and the prion titer by the incubation time assay.

Results

Prn-p0/+ mice, which have about half the normal level of PrPC in their brains, show enhanced resistance to scrapie, as manifested by a significant delay in onset and progression of clinical disease. However, while in wild type animals an increase in prion titer and PrPSc levels is followed within weeks by scrapie symptoms and death, heterozygous Prn-p0/+ mice remain free of symptoms for many months despite similar levels of scrapie infectivity and PrPSc.

Conclusions

Our findings extend previous reports showing an inverse relationship between PrP expression level and incubation time for scrapie. However, contrary to expectation, overall accumulation of PrPSc and prions to a high level do not necessarily lead to clinical disease. These findings raise the question whether high titers of prion infectivity could also persist for long periods under natural circumstances in the absence of clinical symptoms.

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Acknowledgments

We thank S. Prusiner for the R073 antiserum and for the tg(SHaPrP)81 mice and P. Autenried for providing animal facilities. This work was supported by grants from the Kanton of Zürich, the Schweizerische Nationalfonds, and NIH NS22786.

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Author notes

  1. Hansruedi Büeler

    Present address: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA, 02142, USA

  2. Andreas Sailer

    Present address: Molecular Neurobiology Laboratory, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA

Authors and Affiliations

  1. Institut für Molekularbiologie I, Universität Zürich, Hönggerberg, 8093, Zürich, Switzerland

    Hansruedi Büeler, Alex Raeber, Andreas Sailer, Marek Fischer, Adriano Aguzzi & Charles Weissmann

  2. Institut für Neuropathologie, Universitätsspital Zürich, Zürich, Switzerland

    Adriano Aguzzi

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  1. Hansruedi Büeler
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Büeler, H., Raeber, A., Sailer, A. et al. High Prion and PrPSc Levels but Delayed Onset of Disease in Scrapie-Inoculated Mice Heterozygous for a Disrupted PrP Gene. Mol Med 1, 19–30 (1994). https://doi.org/10.1007/BF03403528

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