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Folding and fibril formation of prions
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Gierusz, Leszek A. (2012) Folding and fibril formation of prions. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b2683357~S1
Abstract
Prions diseases are a group of fatal neurodegenerative disorders called the
transmissible spongiform encephalopathies (TSEs), which include bovine
spongiform encephalopathy in cattle, scrapie in sheep and Creutzfeldt-Jakob
disease (CJD) in humans. TSEs are associated with the conversion of normal
cellular form of the prion protein (PrPC) to an altered pathological form (PrPSc).
An important phenomenon known as the species barrier affects prion
transmission, resulting in longer incubation time and lower incidence of disease
upon transfer between species. Another feature of prion diseases is diseasemodulating
polymorphisms in PrP sequence which can alter individual‟s
susceptibility to infection.
This thesis investigates two properties of PrP that may elucidate the mechanisms
underlying both species barrier and disease resistance; (i) effect of diseasemodulating
mutations on folding kinetics of PrP and (ii) impact of diseasemodulating
mutations on formation of PrP fibrils.
Equilibrium and kinetic folding studies demonstrate that the folding pathway of
PrP is affected by mutation Q167R which confers disease resistance, and
mutations S170N, N174T and S170N/N174T characteristic for Chronic Wasting
Disease in cervids, which are known to increase disease susceptibility.
The destabilising effect of Q167R mutation previously observed via equilibrium
folding studies was confirmed through direct kinetic observations. Subsequent
fibrilisation experiments suggested a possible link between the stability of mouse
prion protein and its propensity to form fibrils, elucidating a potential mechanism
of increased disease resistance conferred by Q167R mutation.
Equilibrium folding studies of S170N, N174T and S170N/N174T revealed a
surprising correlation between the structural effects of these mutations and
fibrilisation propensity.
Based on these findings, a disease resistance mechanism centred on decreased
formation of neurotoxic particles in the organism as well as diminished ability of
infectious oligomers from both inside and outside to propagate oligomerisation of
PrP has been proposed.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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Library of Congress Subject Headings (LCSH): | Prions -- Research, Prion diseases -- Pathogenesis, Protein folding, Chemical kinetics | ||||
Official Date: | September 2012 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | School of Life Sciences | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Pinheiro, Teresa | ||||
Sponsors: | Engineering and Physical Sciences Research Council (EPSRC) | ||||
Extent: | xiv, 247 leaves : illustrations, charts. | ||||
Language: | eng |
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