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Mice with gene targetted prion protein alterations show that Prnp, Sinc and Prni are congruent
R C Moore1, J Hope, P A McBride
1Institute of Cell and Molecular Biology, University of Edinburgh, UK.
Abstract:
Classical genetic analysis has identified Sinc/Prni as the major gene controlling mouse scrapie incubation time. Sinc/Prni is linked to Prnp, the gene encoding the prion protein (PrP). Prnp alleles express distinct PrP protein variants, PrP A and PrP B, which arise from codon 108L/F and 189 T/V dimorphisms. Prnp genotype segregates with incubation time length which suggests, but does not prove, that incubation time is controlled by PrP dimorphisms, and that the Sinc/Prni and Prnp loci are congruent. We have used gene targetting to construct mice in which the endogenous Prnp allele has been modified to express PrP B instead of PrP A. Challenge with a mouse-adapted BSE strain results in dramatically shortened incubation times and demonstrates that PrP dimorphisms at codon 108 and/or 189 control incubation time, and that Sinc/Prni and Prnp are congruent.
Insights
Mouse prion protein (PrP) variants control scrapie incubation time. Gene targeting confirmed that PrP dimorphisms at codons 108 and 189 dictate incubation periods, validating the Sinc/Prnp gene linkage.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Classical genetic analysis identified Sinc/Prni as the primary gene influencing mouse scrapie incubation time.
- Sinc/Prni is genetically linked to Prnp, the gene encoding the prion protein (PrP), suggesting a connection between PrP and disease progression.
Purpose of the Study:
- To definitively establish whether PrP dimorphisms at codons 108 and 189 control incubation time.
- To confirm the congruence of the Sinc/Prni and Prnp loci.
Main Methods:
- Gene targeting was employed to create mice with modified endogenous Prnp alleles, expressing PrP B instead of PrP A.
- These genetically modified mice were challenged with a mouse-adapted bovine spongiform encephalopathy (BSE) strain.
Main Results:
- Mice expressing PrP B exhibited significantly shortened incubation times compared to controls.
- This outcome provides direct evidence that PrP dimorphisms at specific codons influence incubation period.
Conclusions:
- Prion protein (PrP) dimorphisms at codons 108 and/or 189 are the key determinants of scrapie incubation time in mice.
- The Sinc/Prni and Prnp loci are indeed congruent, with Prnp variations directly controlling disease kinetics.