Browsing by Person "Ironside, James"

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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.
A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy
(EMBO Press, 1999-12-01) Manson, Jean C.; Jamieson, Elizabeth; Baybutt, Herbert; Tuzi, Nadia L.; Barron, Rona; McConnell, Irene; Somerville, Robert; Ironside, James; Will, Robert; Sy, Man-Sun; Melton, David W.; Hope, James; Bostock, Christopher
A mutation equivalent to P102L in the human PrP gene, associated with Gerstmann–Straussler syndrome (GSS), has been introduced into the murine PrP gene by gene targeting. Mice homozygous for this mutation (101LL) showed no spontaneous transmissible spongiform encephalopathy (TSE) disease, but had incubation times dramatically different from wild-type mice following inoculation with different TSE sources. Inoculation with GSS produced disease in 101LL mice in 288 days. Disease was transmitted from these mice to both wild-type (226 days) and 101LL mice (148 days). In contrast, 101LL mice infected with ME7 had prolonged incubation times (338 days) compared with wild-type mice (161 days). The 101L mutation does not, therefore, produce any spontaneous genetic disease in mice but significantly alters the incubation time of TSE infection. Additionally, a rapid TSE transmission was demonstrated despite extremely low levels of disease-associated PrP.