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Mice devoid of PrP are resistant to scrapie
Abstract:
S.B. Prusiner proposed that the infectious agent of scraple, 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 13 months while wild-type controls all died within 6 months. 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 PrPC is essential for susceptibility. Introducing foreign prion genes also altered disease resistance, highlighting prion homology
Area of Science:
- Neuroscience
- Molecular Biology
- Infectious Diseases
Background:
- Scrapie is a fatal neurodegenerative disease caused by prions.
- Prions are infectious proteins, specifically PrPSc, a misfolded form of the normal cellular prion protein, PrPC.
- The role of PrPC in scrapie pathogenesis is critical.
Purpose of the Study:
- To investigate the necessity of the normal prion protein (PrPC) for scrapie susceptibility.
- To determine the effect of PrPC gene knockout on disease development.
- To explore the influence of prion homology on disease transmission.
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 symptom development and survival rates.
Main Results:
- PrPC-deficient mice remained asymptomatic for over 13 months post-inoculation, unlike wild-type controls that died within 6 months.
- 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:
- The normal cellular prion protein (PrPC) is required for typical susceptibility to prion diseases like scrapie.
- Lack of homology between the infectious prion and the host PrP gene significantly retards disease progression.
- These findings underscore the critical role of PrPC in prion replication and disease.
