Browsing by Person "Thomson, Val"

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The 101L mutation in murine PrP can alter transmission across three species barriers
(2002) Barron, Rona; Jamieson, Elizabeth; Thomson, Val; Melton, David W.; Will, Robert; Ironside, James; Manson, Jean C.
Changing a single amino acid in the N-terminus of murine PrP alters incubation time across three species barriers
(EMBO Press, 2001-09-17) Barron, Rona; Thomson, Val; Jamieson, Elizabeth; Melton, David W.; Ironside, James; Will, Robert; Manson, Jean C.
The PrP gene of the host exerts a major influence over the outcome of transmissible spongiform encephalopathy (TSE) disease, but the mechanism by which this is achieved is not understood. We have introduced a specific mutation into the endogenous murine PrP gene using gene targeting to produce transgenic mice with a single amino acid alteration (proline to leucine) at amino acid position 101 in their PrP protein (P101L). The effect of this alteration on incubation time, targeting and PrPSc formation has been studied in TSE-infected animals. Transgenic mice carrying the P101L mutation in PrP have remarkable differences in incubation time and targeting of central nervous system pathology compared with wild-type littermates, following inoculation with infectivity from human, hamster, sheep and murine sources. This single mutation can alter incubation time across three species barriers in a strain-dependent manner. These findings suggest a critical role for the structurally ‘flexible’ region of PrP in agent replication and targeting of TSE pathology.
Transmission of murine scrapie to P101L transgenic mice
(Microbiology Society, 2003-11-01) Barron, Rona; Thomson, Val; King, Declan; Melton, David W.; Manson, Jean C.
The PrP protein is central to the transmissible spongiform encephalopathies (TSEs), and the amino acid sequence of this protein in the host can influence both incubation time of disease and targeting of disease pathology. The N terminus of murine PrP has been proposed to be important in the replication of TSE agents, as mutations or deletions in that region can alter the efficiency of agent replication. To address this hypothesis and to investigate the mechanisms by which host PrP sequence controls the outcome of disease, we have assessed the influence of a single amino acid alteration in the N-terminal region of murine PrP (P101L) on the transmission of TSE agents between mice. Mice homozygous for the mutation (101LL) were inoculated with TSE strains 139A and 79A derived from mice carrying a Prnpa allele, and 79V and 301V derived from mice carrying a Prnpb allele. Incubation times in 101LL mice were extended with all four strains of agent when compared with those in the corresponding mouse genotype from which the infectivity was derived. However, the degree to which the incubation period was increased showed considerable variation between each strain of agent. Moreover, the presence of this single amino acid alteration resulted in a 70 day reduction in incubation time of the 301V strain in Prnpa mice. The effect of the 101L mutation on murine scrapie incubation time appears therefore to be strain specific.