McKinnon, CA; (2013) The Role of the Ubiquitin-Proteasome System in Prion Disease Pathogenesis. Doctoral thesis , UCL (University College London).

Abstract

Prion diseases are a group of fatal neurodegenerative disorders characterised by the accumulation of misfolded prion protein (PrPSc) in the brain. They are caused by the conformational rearrangement of the normal cellular protein, PrPC, to the abnormal isoform PrPSc. The critical relationship between aberrant protein misfolding and neurotoxicity currently remains unclear. The aim of this Thesis was to investigate the role of the ubiquitin-proteasome system (UPS) in prion disease pathogenesis. The UPS is a tightly regulated system for the identification and subsequent degradation of misfolded or redundant proteins by the 26S proteasome. Previous in vitro studies have identified a direct inhibitory interaction between misfolded PrP isoforms and the proteasome. To evaluate whether UPS dysfunction plays a significant role in vivo, a detailed time-course study was carried out in prion-infected UbG76V-GFP proteasome reporter mice. This work revealed a spatiotemporal correlation between the accumulation of PrPSc and the onset of UPS dysfunction in neurons and astrocytes. UPS impairment was shown to occur prior to the onset of behavioural dysfunction and neuronal loss, underlining that upregulation of the UPS may be an important therapeutic approach for the treatment of prion diseases. To test this theory, a novel recombinant adeno-associated viral vector was developed to attempt upregulation of the UPS in vivo by overexpression of the 19S regulatory particle subunit PSMD11. In parallel with in vivo studies, work in this Thesis aimed to develop a neural stem cell line expressing an epitope-tagged PrPC chimera (PrP-224AlaMYC) which can be differentiated into a mixed population of neurons and astrocytes. Since previous cell models of prion infection have utilised immortalised neuroblastoma cells which do not exhibit prion-induced cell death, the development of this post-mitotic cell system could provide important insights into how PrPSc gains access to the cytosolic compartment to interact with the UPS.

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