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Dietetics, Nutrition and Biological Sciences

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Author: search.filters.author.Manson, Jean C.

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Now showing 1 - 10 of 22
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    A gene-targeted mouse model of P102L Gerstmann-Sträussler-Scheinker syndrome
    (Elsevier, 2003-03) Barron, Rona; Manson, Jean C.
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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.
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    Gene Targeting the PrP Gene
    (Horizon Bioscience, 2004) Barron, Rona; Manson, Jean C.
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    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.
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    The transmissible spongiform encephalopathies.
    (Cambridge University Press, 2005-04) Manson, Jean C.; Barron, Rona; Diggard, P.; Nash, A.A.; Randall, R.E.
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    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.
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    The transmissible spongiform encephalopathies: emerging and declining epidemics
    (Portland Press, 2006-10-25) Manson, Jean C.; Cancellotti, Enrico; Bishop, Matthew T.; Hart, Patricia; Barron, Rona
    TSEs (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.
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    Insights into Mechanisms of Chronic Neurodegeneration
    (MDPI, 2016-01-12) Diack, Abigail B.; Alibhai, James D.; Barron, Rona; Bradford, Barry; Piccardo, Pedro; Manson, Jean C.
    Chronic neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and prion diseases are characterised by the accumulation of abnormal conformers of a host encoded protein in the central nervous system. The process leading to neurodegeneration is still poorly defined and thus development of early intervention strategies is challenging. Unique amongst these diseases are Transmissible Spongiform Encephalopathies (TSEs) or prion diseases, which have the ability to transmit between individuals. The infectious nature of these diseases has permitted in vivo and in vitro modelling of the time course of the disease process in a highly reproducible manner, thus early events can be defined. Recent evidence has demonstrated that the cell-to-cell spread of protein aggregates by a “prion-like mechanism” is common among the protein misfolding diseases. Thus, the TSE models may provide insights into disease mechanisms and testable hypotheses for disease intervention, applicable to a number of these chronic neurodegenerative diseases.
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    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.
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    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.