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Title: Transmissible spongiform encephalopathy : the relationship between PrPsc and infectivity in murine models
Author: Campbell, Susan L.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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A murine model of TSE had been produced in which the brains of infected animals, at disease end-point, exhibit very low levels of PrPSc, and in which infectivity can be further transmitted in short incubation times. This is contradictory to the prion hypothesis. Using bioassay, the titre of infectivity in brain from 3 animals of this model was measured. Other murine TSE models exhibiting high and intermediate levels of PrPSc in brain at disease end-point were compared with the low PrPSc model. The low PrPSc model displayed infectivity titres of a similar value to the high and intermediate PrPSc models. Furthermore, disease was transmitted from the low PrPSc model with shorter incubation times than from models with high and intermediate PrPSc levels. PrPSc levels in protease-treated brain homogenate were semi-quantatively measured using immunoblots. PrPSc levels in the low model were 8 to 32 times lower than found in the high PrPSc model, however surprisingly levels of total PrP (PrPC and PrPSc) were the same in all models. Therefore low PrPSc levels in the low model were not due to a reduced amount of PrP produced during disease in these animals. This suggested that infectivity in brain tissue of the low PrPSc model could possibly be associated with another form of PrP, not PrPSc, therefore investigation of alternative forms of PrP that might be responsible for infectivity in the low PrPSc model was undertaken. No evidence of increased amounts of transmembrane PrP was found in infected animals from the low PrPSc model. Further biochemical examination of the protease resistance and detergent solubility of PrP in infected animals, using proteinase-K (PK) treatment and solubilisation with sarkosyl, revealed the presence of protease-resistant, detergent insoluble PrPSc from the high and intermediate PrPSc models. In the low PrPSc model where infectivity was transmitted, one animal possessed protease-resistant, detergent insoluble PrPSc and two revealed only the protease-sensitive, detergent-soluble PrPC normally found in infected animals. In conclusion, contrary to the prion hypothesis, murine TSE models can transmit infectivity from brain tissue in which PrPSc levels are extremely low or non-detectable. Furthermore, this tissue can contain a high titre of infectivity. Alternative forms of PrP have been implicated in TSE disease, however no evidence of alternative PrP was found in the models investigated. Given that some infectious brain tissue only contained PrP with PrPC-like characteristics, PrPSc may not be the infectious agent of TSE. It may be possible that a form of PrP similar to PrPC is infectious, but it is also conceivable that a molecule other than PrP, not studied herein, is the infectious agent.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available