Browsing by Person "Manson, Jean"

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How does host PrP control TSE disease?
(Springer, 2004-05) Manson, Jean; Barron, Rona; Tuzi, Nadia L.; Baybutt, Herbert; Bishop, Matthew; Cancellotti, Enrico; Hart, Patricia; Jamieson, L.; Aitchison, L.; Gall, E.; Bradford, Barry; King, Declan
PrP is central to the TSE disease process and has been hypothesised to be the infectious agent. Polymorphisms in the PrP gene of a number of species 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. In order 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. This strategy therefore allows the effect of specific mutations in the PrP gene to be assessed. We have introduced mutations into the Prnp gene which prevent glycosylation at each or both of the two N-linked glycosylation sites of PrP and are using TSE infection of these mice to investigate the role of PrP glycosylation in strain targeting and strain determination. We have investigated the role of the sequence of the host PrP gene in determining susceptibility by inserting point mutations or replacing the murine PrP gene with that of human or bovine PrP. This has produced a model of TSE disease which contains high levels of infectivity in the absence of PrPSc and we are using this model to determine the nature of the infectious agent. We have thus established that the gene targeting approach can produce models for TSE disease which address fundamental questions associated with these diseases. We aim to use these models to address central issues including the origin of strains, the species barrier and the nature of the infectious agent.
Molecular Barriers to Zoonotic Transmission of Prions
(2014-01) Barria, Marcelo A.; Balachandran, Aru; Morita, Masanori; Kitamoto, Tetsuyuki; Barron, Rona; Manson, Jean; Knight, Richard; Ironside, James W.; Head, Mark W.
The risks posed to human health by individual animal prion diseases cannot be determined a priori and are difficult to address empirically. The fundamental event in prion disease pathogenesis is thought to be the seeded conversion of normal prion protein to its pathologic isoform. We used a rapid molecular conversion assay (protein misfolding cyclic amplification) to test whether brain homogenates from specimens of classical bovine spongiform encephalopathy (BSE), atypical BSE (H-type BSE and L-type BSE), classical scrapie, atypical scrapie, and chronic wasting disease can convert normal human prion protein to the abnormal disease-associated form. None of the tested prion isolates from diseased animals were as efficient as classical BSE in converting human prion protein. However, in the case of chronic wasting disease, there was no absolute barrier to conversion of the human prion protein.
Molecular Model of Prion Transmission to Humans
(Centers for Disease Control and Prevention, 2009-12) Jones, Michael; Wight, Darren; Barron, Rona; Jeffrey, Martin; Manson, Jean; Prowse, Christopher; Ironside, James W.; Head, Mark W.
To assess interspecies barriers to transmission of transmissible spongiform encephalopathies, we investigated the ability of disease-associated prion proteins (PrPd) to initiate conversion of the human normal cellular form of prion protein of the 3 major PRNP polymorphic variants in vitro. Protein misfolding cyclic amplification showed that conformation of PrPd partly determines host susceptibility.
A single amino acid alteration in murine PrP dramatically alters the TSE incubation time
(Springer, 2000) Manson, Jean; Barron, Rona; Jamieson, Elizabeth; Baybutt, Herbert; Tuzi, Nadia L.; McConnell, I.; Melton, David W.; Hope, J.; Bostock, C.
In order to investigate mutations linked to human TSEs, we have used the technique of gene targeting to introduce specific mutations into the endogenous murine PrP gene which resulted in a P101L substitution (Prnp a101L) in the murine PrP gene. This mutation is equivalent to the 102L mutation in the human PrP gene which is associated with Gerstmann-Sträussler syndrome. Since the mutated gene is in the correct chromosomal location and control of the mutant gene expression is identical to that of the wild type murine PrP gene, the precise effect of the 101L mutation in the uninfected and TSE infected mouse can be investigated in this transgenic model. Mice homozygous for this mutation (101LL) while showing no spontaneous TSE disease were more susceptible to TSE disease than wild type mice following inoculation with GSS infectivity. Disease was transmitted from these mice to mice both with and without the Prnp a101L allele. The 101L mutation does not therefore produce spontaneous genetic disease in mice but does dramatically alter incubation periods following TSE infection. Additionally, a rapid TSE transmission was demonstrated associated with extremely low amounts of PrPSc.