Dietetics, Nutrition and Biological Sciences
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Item A gene-targeted mouse model of P102L Gerstmann-Sträussler-Scheinker syndrome(Elsevier, 2003-03) Barron, Rona; Manson, Jean C.Item 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.Item Gene Targeting the PrP Gene(Horizon Bioscience, 2004) Barron, Rona; Manson, Jean C.Item Knockouts, Knockins, Transgenics and Transplants in Prion Research(Cold Spring Harbor Laboratory Press, 2004) Weissman, C; Fleschig, E; Barron, Rona; Aguzzi, A; Manson, Jean C.Item The transmissible spongiform encephalopathies.(Cambridge University Press, 2005-04) Manson, Jean C.; Barron, Rona; Diggard, P.; Nash, A.A.; Randall, R.E.Item The role of host PrP in control of incubation time(Springer Verlag, 2005) Manson, Jean C.; Barron, Rona; Hart, Patricia; Tuzi, Nadia L.; Bishop, Matthew T.PrP is central to TSE disease and has been hypothesised to be the infectious agent. Polymorphisms in the PrP gene are associated with different incubation times of disease following exposure to an infectious agent and mutations in the human PrP gene can apparently lead to spontaneous genetic disease. Strains of TSE agent are proposed to be generated and maintained through differences in glycosylation or conformation of PrP and the barrier to infection between species is thought to be due to the differences in the sequence of PrP between different species. To test these hypotheses, we have introduced specific modifications into the endogenous mouse Prnp gene by gene targeting. The mutated PrP gene is in the correct location under the control of the endogenous Prnp regulatory sequences and thus expressed in the same tissues and amounts as the wild type Prnp gene. By altering the murine PrP coding region to that of another species we have established that increasing overall identity between host and donor PrP can lead to either an increase or a decrease in incubation time of disease in a strain dependent manner. We have introduced a point mutation (101L) into the N-terminus of the host PrP and shown that it dramatically changes the susceptibility of the host to infection from different species. We have in addition demonstrated that polymorphisms in the N terminus (L108T) and C-terminus (F189V) of host PrP both alter the incubation time of disease. We have in addition introduced mutations into the Prnp gene which prevent glycosylation at each or both of the two N-linked glycosylation sites of PrP. Inoculation of these mice with infectivity has established that glycosylation of host PrP can influence incubation time of disease, vacuolar pathology and strain determination.Item The transmissible spongiform encephalopathies: emerging and declining epidemics(Portland Press, 2006-10-25) Manson, Jean C.; Cancellotti, Enrico; Bishop, Matthew T.; Hart, Patricia; Barron, RonaTSEs (transmissible spongiform encephalopathies) are neurodegenerative diseases of various mammalian species, the best known of which include BSE (bovine spongiform encephalopathies) in cattle, CJD (Creutzfeldt–Jakob disease) in humans, scrapie in sheep and CWD (chronic wasting disease) in deer. This review examines the emergence of various TSE strains and their transmission, and discusses disease surveillance and control.Item 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, ChristopherA 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.Item 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.Item 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.