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PrP-deficient mice are resistant to scrapie
C Weissmann1, H Büeler, M Fischer
1Institut für Molekularbiologie I, Universität Zürich, Switzerland.
Abstract:
Prusiner proposed that the infectious agent of scrapie, the prion, is PrPSc, a modified form of the normal host protein PrPC. Prn-p0/0 mice devoid of PrPC showed normal development and behavior. When inoculated with mouse scrapie prions they remained free of scrapie symptoms for at least 16 months while wild type controls all died within 6 months. Propagation of infectivity in the PrP null mice, if any, was less than 10(-5) that in wild type animals. Surprisingly, heterozygous Prn-p0/+ mice also showed enhanced resistance to scrapie. After introduction of Syrian hamster PrP transgenes, Prn-p0/0 mice became highly susceptible to hamster but not to mouse prions. These experiments show that PrPC, possibly at close to normal levels, is required for the usual susceptibility to scrapie and that lack of homology between incoming prions and the host's PrP genes retards disease.
Insights
Mice lacking the normal prion protein (PrPC) resisted scrapie infection, demonstrating its necessity for disease susceptibility. Introducing foreign prion genes further highlighted the role of PrPC homology in prion disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Infectious Diseases
Background:
- Prions are infectious agents composed of misfolded prion proteins (PrPSc).
- The normal cellular prion protein (PrPC) is encoded by the host gene.
- The role of PrPC in prion disease pathogenesis has been investigated.
Purpose of the Study:
- To investigate the role of PrPC in susceptibility to prion diseases.
- To determine if PrPC is essential for prion propagation.
- To examine the effect of PrPC homology on prion disease.
Main Methods:
- Generation of PrPC-deficient (Prn-p0/0) and heterozygous (Prn-p0/+) mice.
- Inoculation of these mice with mouse-adapted scrapie prions.
- Introduction of Syrian hamster PrP transgenes into Prn-p0/0 mice.
- Assessment of scrapie symptoms and prion infectivity propagation.
Main Results:
- Prn-p0/0 mice showed normal development and behavior, and were highly resistant to mouse scrapie.
- Scrapie infectivity propagation in Prn-p0/0 mice was significantly reduced compared to wild-type controls.
- Heterozygous Prn-p0/+ mice exhibited enhanced resistance to scrapie.
- Prn-p0/0 mice expressing Syrian hamster PrP became susceptible to hamster prions but not mouse prions.
Conclusions:
- PrPC is essential for normal susceptibility to prion diseases like scrapie.
- Lack of homology between the infectious prion and host PrP significantly retards disease.
- These findings support the prion hypothesis and highlight the importance of PrPC in disease