In Vitro analysis of the molecular basis of strain variation in scrapie

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The existence of TSE strains challenges the prion hypothesis. Even if reports of de novo generation of mammalian prions are correct, it is still not easy to explain TSE strains by a protein-only model. We need new information about how TSE strains are enciphered at a molecular level. This project will use cells, known to support infection by different TSE strains, to prepare fractions for use in our cell free conversion assay to stimulate the production of protease-resistant protein from recombinant PrP, seeding the reaction with several different, well-characterised TSE strains. In parallel, we will investigate whether there exist different molecules associated with PrPSc purified from the different TSE strains by chromatographic and mass spectrometric analsyes of protein and non-protein samples. Ultimately, we aim to define cellular fractions or molecules that can be incubated with recombinant PrP in unseeded fibrillisation assays to produce fibrils that mimic various TSE strains.

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