Prion Mouse Model
The mouse is commonly chosen as a model organism for research because of its small size, short generation time, and its proficiency to breed in captivity. Most importantly, mouse shares the genetic similarity with human. If we understand the disease progression in mice whose environment, genetic background, and disease onset are controlled, it will facilitate us identifying the molecules playing key roles in determining pathophysiology in humans based on their counterparts in mice whose expression levels are altered after prion infection.
The strategy for identification of core differentially expressed genes (DEGs) and their functional analysis in mouse prion diseases is shown in Figure 1. Two prion strains (RML and 301V) were used for inoculating mice from six different genetic backgrounds (B6, B6.I, FVB, Tg4053, 0/+, and 0/0) to generate eight prion-mouse combinations. From the list of 7400 DEGs identified from at least one of the five combinations with normal levels of prion protein (1X), 333 DEGs shared by all five were selected through novel statistical methods to represent perturbed networks essential to prion pathophysiology. The Venn diagram shows the overlap of the 333 DEGs with DEGs from Tg4053-RML (mice expressing eight times of normal prion protein levels) and from 0/+ -RML (mice expressing one-half of normal prion protein levels). Among 333 DEGs, 161 genes were mapped to networks through protein-protein interaction networks or metabolic pathways. Also, by comparison of 333 DEGs with previous prion microarray studies, we identified 178 DEGs that have not been reported in connection with prion disease.
Figure 1. Overview of prion strains and mouse strains used in the identification of core DEGs in mouse prion disease. This figure was taken from Hwang, D. et al. (2009) A Systems Approach to Prion Disease. Molecular Systems Biology.
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|PDDB Name||Mouse Strain||PrP Genotype||Prion Strain||End Point(d/w)||Harvest Interval|
|FVB.Prnp0/0, RML||FVB.129-Prnptm1Zrch||0/0||RML||no illness||-|
|FVB.Prnp0/+, RML||(FVB x FVB.129-Prnptm1Zrch)||a/0||RML||~400d/57w||4w|
|-||(FVB x FVB.129-Prnptm1Zrch)||a/0||none||no illness||-|
|Tg(MoPrP-A)B4053, RML||Tg(MoPrP)B4053||>30 a||RML||~60d/8w||1w|
|-||Tg(MoPrP)B4053||>30 a||none||no illness||-|
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The Prnp "a" allele encodes PrP with codons 108 Leu and 189 Thr, while the "b" allele encodes Prnp with codons 108 Phe and 189 Val. The genotype at this locus is one important factor among several that determine incubation time for a variety of prion strains.
Multiple research experiments have shown that mice lacking the Prnp gene (genotype "0/0") fail to get prion disease even though they have been chronically exposed to the infectious scrapie prion protein. The double knock-out mutant serves as the control in dissecting the mechanisms of prion disease taking place in the Prnpa and Prnpb genotypes. It provides additional information required to understand prion infection, because it enables differentiation between prion infection-specific processes and general cellular processes.
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Mice inoculated with prion-infected (301V or RML) brain homogenate were compared to mice that were inoculated with clean brain homogenate or to mice that were not inoculated at all.
The RML prion strain is a mouse-adapted prion strain derived from sheep infected with Scrapie by W. Hadlow at the Rocky Mountain Laboratories in Hamilton, Montana.
The 301V prion strain is a mouse-adapted prion strain derived from cows infected with Bovine Spongiform Encephalopathy (BSE) by H. Fraser at the Institute for Animal Health in the United Kingdom.
The experiments outlined in the table provide the opportunity to assess effects of both PrP and other host genes in prion pathology using congenic and genetically engineered mice.
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