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Title: Development of an in vitro assay of prion-induced neurotoxicity
Author: Reilly, Madeleine Louise
ISNI:       0000 0004 8508 1988
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Prion diseases involve the structural corruption of monomeric cellular prion protein, which aggregates as pathogenic fibrillary PrP assemblies that spread through the brain. How these processes lead to fatal neurodegeneration in prion disease remains one of the most challenging questions in biology with wide relevance to other neurodegenerative diseases involving pathogenic fibrillary assemblies of other host proteins. There is an established model of prion propagation due to the availability of precise cellular assays of infectivity. However, the kinetics of prion-associated toxicity is not defined as there are no robust methods to accurately quantify toxicity in vitro. In this study, automatic image analysis algorithms that measure multiple parameters of neurotoxicity were developed and validated for the detection of prion-associated toxicity in primary cortical-hippocampal neurons. The analysis system defines a dynamic range where prion-infected brain homogenate is more toxic than mock-infected control and requires the expression of the cellular prion protein (PrPC). This thesis reports: a longitudinal study of prion-induced neurotoxicity by assaying prion-infected samples collected over time; that authentically infectious ex vivo prions are not directly responsible for prion disease neurotoxicity; and that ICSM18, an anti-PrPC mouse monoclonal antibody known to cure prion infections, is not inherently neurotoxic and blocks prion-induced toxicity. The robust, highly automated analysis described here provides a platform to isolate and purify putative toxic species from prion-infected brains and will facilitate identifying drug targets and screening of candidate therapeutics for prion disease. This thesis highlights two significant findings: for the first time, that anti-PrP immunotherapeutics may have a two-pronged role for the treatment of prion disease - curing prion propagation and blocking neurotoxicity and that infectious prions are not inherently neurotoxic, challenging the long-standing conviction that infectious prions are directly responsible for neurodegeneration in prion disease and substantiating a current model of uncoupled infectious and toxic species production.
Supervisor: Jat, P. ; Collinge, J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available