Browsing by Person "Bishop, Matthew T."

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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.
The role of host PrP in Transmissible Spongiform Encephalopathy
(Elsevier, 2007-06) Cancellotti, Enrico; Barron, Rona; Bishop, Matthew T.; Hart, Patricia; Wiseman, Patricia; Manson, Jean C.
PrP has a central role in the Transmissible Spongiform Encephalopathies (TSEs), and mutations and polymorphisms in host PrP can profoundly alter the host's susceptibility to a TSE agent. However, precisely how host PrP influences the outcome of disease has not been established. To investigate this we have produced by gene targeting a series of inbred lines of transgenic mice expressing different PrP genes. This allows us to study directly the influence of the host PrP gene in TSEs. We have examined the role of glycosylation, point mutations, polymorphisms and PrP from different species on host susceptibility and the disease process both within the murine species and across species barriers.
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.