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Title: The biology of aggregate-prone proteins and possible therapeutic interventions against their toxicity
Author: Berger, Z.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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The main aim of my project was to investigate pathways involved in protecting against the toxicity caused by different aggregate-prone proteins and to explore possible therapeutic interventions. My strategy was to generate a Drosophila model expressing a stretch of long polyalanines. This model can be used along with models of polyglutamine diseases to study various pathways in the context of different aggregate-prone proteins. In, addition, generation of this model will also help to better understand the toxicity of long polyalanines. My results show that expanded polyalanines are toxic in vivo in Drosophila and this is accompanied by aggregate formation. This suggests that polyalanines can cause diseases by a gain-of-function mechanism in vivo and that this mechanism should be considered for all diseases caused by expanded polyalanines. In order to investigate if manipulation of the Wnt and TOR pathway would be beneficial in the context of different aggregate-prone proteins in vivo, I used fly models of these disorders. Inhibition of GSK3 using lithium and a GSK3-specific inhibitor decreased toxicity of both proteins and similar effects were seen when downstream targets were manipulated in vivo. Inhibition of TOR by rapamycin decreased toxicity of proteins with long polyglutamines and polyalanines in vivo and this in vivo effect can be largely attributed to the induction of autophagy. Rapamycin also reduces toxicity of wild-type and mutant tau in vivo and these effects can be accounted for by reductions in insoluble tau. Thus, lithium, GSK3-specific inhibitors and rapamycin may be a beneficial therapeutic strategy in diseases associated with different aggregate-prone proteins.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available