How does host PrP control TSE disease?

Jean Manson, Rona Barron, Nadia L. Tuzi, Herbert Baybutt, Matthew Bishop, Enrico Cancellotti, Patricia Hart, L. Jamieson, L Aitchison, E. Gall, Barry Bradford, Declan King

Research output: Chapter in Book/Report/Conference proceedingConference contribution


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.
Original languageEnglish
Title of host publicationJournal of Neurovirology
EditionSupp 3
Publication statusPublished - May 2004
EventPrion 2004 - Paris, France
Duration: 24 May 200428 May 2004


ConferencePrion 2004


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