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 The nature of the prion(2009) Barron, RonaItem The relationship between PrPSc and TSE infectivity(Research Signpost, 2011) Barron, RonaItem 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.