Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.663962
Title: Glycosylation of PrP and the transmissible spongiform encephalopathies species barrier
Author: Wiseman, F. K.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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Abstract:
In vitro conversion experiments have suggested that PrPCs N-glycans specifically retard the cross species PrPSc seeded conversion of PrPC, suggesting that glycosylation of PrPC play a specific TSE species barrier role. To test this hypothesis, gene-targeted PrP glycosylation deficient transgenic mice in which the first, second or both glycan attachment sites are disrupted by amino acid substitution(s), were challenged with non-murine TSE agents. The incidence of clinical disease and subclinical TSE specific pathology, including PrPSc formation differed between the glycosylation deficient transgenics and normally glycosylated controls, demonstrating that glycosylation of PrPC affects the TSE species barrier. Moreover, both the site of N-glycan attachment and the TSE strain influenced the role of PrP glycosylation state. Additionally, these transgenic mice were shown not to spontaneously develop TSE disease nor adopt PrPSc-like properties in the absence of a TSE challenge. Hence, validating them as a model system in which to study TSE transmission and demonstrating that the absence of PrP’s N-glycans does not lead to the spontaneous formation of PrPSc in vivo. The subcellular localisation of PrPC was altered in transgenic mice in which PrP lacked both of its N-glycosylation sites, suggesting a possible mechanism for the enhanced resistance of these transgenics to cross species TSE challenge. An in vitro conversion assay was used to demonstrate that the importance of the first N-glycan attachment site to cross species TSE transmission can be attributed to a direct effect on the convertibility of PrPC. However, the enhanced susceptibility of transgenic mice lacking the second glycosylation site to cross species TSE challenge is not due to an increase in PrPSc misfolding efficiency. This suggests that other aspects of PrP biology, such as PrPSc toxicity or clearance, are influenced by PrP glycosylation state and that these can have a major impact on TSE disease outcome.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.663962  DOI: Not available
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