Moonga, J; (2012) In vivo dissection of the role of the ubiquitin proteasome system in the pathogenesis of prion disease. Doctoral thesis , UCL (University College London).

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Abstract

Prion diseases comprise a group of fatal neurodegenerative disorders caused by the conformational re-arrangement of a normal host-encoded prion protein, PrPC, to an abnormal infectious isoform, PrPSc. Currently, the precise cellular mechanism(s) of prion-mediated neurodegeneration remain unclear. However, increasing evidence suggests a role for the ubiquitin proteasome system (UPS) in prion disease pathogenesis, with a direct functional impairment of the 26S proteasome leading to the accumulation of UPS substrates in the brains of prion-infected mice. The UPS functions to regulate the targeted degradation of intracellular proteins and maintain cellular proteostasis. Alterations in proteasome proteolysis have been shown to contribute to the build up of proteins associated with aging and dysregulation of the UPS has been linked to several neurodegenerative diseases. The principal aim of this thesis was to characterise the progression of UPS dysfunction in vivo in the brains of prion-infected mice using a ubiquitin-GFP reporter mouse model. Using the UbG76V-GFP transgenic mouse model, UPS dysfunction was observed in the brain early in the prion disease incubation period, before key hallmarks of disease pathology were observed. The accumulation of Ub-GFP reporter coincided with markers of prion disease neuropathology, such as PrPSc deposition and extensive astrogliosis. The majority of cells in which the Ub-GFP reporter was observed in the thalamus appeared to be astrocytes, suggesting that altered proteolysis and reactive astrocyte pathology may be linked. Ubiquitin levels were increased significantly in the brains of prion infected mice, while 26S proteasome peptidase activity was reduced. Behavioural abnormalities and motor skills deficits were also observed in prion-infected UbG76V-GFP mice, which may correlate to neuronal loss and/or synaptic dysfunction associated with impairment of the UPS machinery. Collectively, the data presented in this thesis provide evidence of an early and potentially important role for UPS dysfunction in prion disease pathogenesis.

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