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Title: Conditional proteasome gene deletion : molecular neuropathology and the pathogenesis of Parkinson’s disease
Author: Paine, Simon Marcus Liddell
ISNI:       0000 0004 2745 8003
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2012
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Parkinson's disease is an archetypal sporadic neurodegenerative disease: it is age-related and results in region-specific neurodegeneration with intracellular inclusions in many of the remaining neurones. Despite three decades of intense study, disease modifying therapies remain beyond the horizon, reflecting our understanding of the pathological process and the intrinsic challenges that the degenerative diseases of the brain present. Dysfunction in a number of cellular systems has been implicated in the development of Parkinson's disease. Protein homeostasis in terminally differentiated neurones is of particular import; unlike most other cells, they have no progeny with which to gift troublesome proteins. The ubiquitin proteasome system is the cell's main regulated proteolytic pathway and observations from neuropathological, genetic and animal studies have consistently found evidence that it may be aetiologically important in Parkinson's disease. Using a Cre/loxP approach Psmc1, which encodes an essential component of the 26S proteasome, was spatially deleted in catecholaminergic neurones in mice. This model reproduced both the region-specific neuronal loss and intraneuronal inclusions that define the sporadic human disease. In this work, I describe the further characterization of this unique model and use it to test hypotheses regarding the nature of the process that leads to these neuropathological features. Specifically, I show that in response to Psmcl deletion genes encoding sub- units of the 26S proteasome are up-regulated; using whole-genome microarray analysis I identify differentially expressed transcripts in micro dissected brain regions and then use the model to demonstrate that α-synuclein is not essential for the neurodegeneration or inclusion formation that result from Psmc1 deletion. These data underline the relevance of this model to the study of the pathogenesis of Parkinson's disease and identify avenues for further investigation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available