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Title: The protective function of the oxidation resistance 1 gene in ALS
Author: Williamson, Matthew
ISNI:       0000 0004 7966 3025
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by the selective degeneration of motor neurons in the brain and spinal cord, resulting in muscle wasting, paralysis and eventually death usually within 2-5 years of symptom onset. Despite decades of intense research to ultimately find a cure, there are still only a few treatments available to patients, none of which are effective in slowing disease progression. Therefore, novel therapeutic strategies will be increasingly important to alleviate this health burden. While the underlying pathogenic mechanisms remain unclear, increasing evidence suggests that oxidative stress (OS) is a key contributory factor early in ALS pathology. Therefore, understanding the role of proteins involved in antioxidant defence networks will facilitate the development of new therapeutic approaches. Oxidation resistance 1 (OXR1) has emerged as an essential antioxidant protein that regulates neuronal survival in response to OS, however its precise molecular functions remain unclear. Thus, the overall aim of this thesis was to investigate the neuroprotective function of Oxr1 in motor neurons, particularly focusing on its role in modulating disease-relevant phenotypes observed in ALS. To ascertain the importance of Oxr1 to motor neuron function and survival, mice in which Oxr1 was conditionally deleted in motor neurons were behaviourally and pathologically characterised. My data indicates that loss of Oxr1 specifically in motor neurons does not increase their susceptibility to degeneration or cause motor dysfunction in aged mice, but can induce a local neuroinflammatory response in the spinal cord. Next, to investigate the neuroprotective function of Oxr1 in ALS caused by mutations in TAR DNA-binding protein 43 (TDP-43), longitudinal behavioural and pathological analysis was carried out on a novel mutant TDP-43 mouse model of ALS in the presence or absence of increased Oxr1 expression. I demonstrate that neuronal overexpression of Oxr1 protects against motor dysfunction and neuromuscular defects in TDP-43 mutant mice. Furthermore, using primary motor neurons from TDP-43 mutant mice, I show that overexpression of Oxr1 can reduce the mislocalisation of TDP-43 protein, which is a characteristic feature in more than 95% of ALS cases. Finally, in order to begin to determine whether endogenous Oxr1 expression can be manipulated as a therapeutic strategy, I investigated its transcriptional regulation by characterizing Oxr1 promoter regions. I identified a highly conserved functional promoter region of Oxr1 that was subsequently used in establishing a new cell-based luciferase reporter assay that can be employed to identify compounds that upregulate Oxr1. Taken together, these studies deepen our understanding of Oxr1 as a neuroprotective antioxidant protein and offers new insights into its potential use as a future therapeutic target for the treatment of ALS.
Supervisor: Davies, Kay ; Oliver, Peter Sponsor: Motor Neurone Disease Association
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available