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The Investigation of Oxidative Damage to Nucleic Acids during Ageing and Motor Neuron Disease

Richardson, Katie (2013) The Investigation of Oxidative Damage to Nucleic Acids during Ageing and Motor Neuron Disease. PhD thesis, University of Sheffield.

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Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder, characterised by the degeneration of upper and lower motor neurons. Multiple mechanisms have been associated with ALS pathology, however the precise molecular events leading to selective motor neuron degeneration have yet to be understood. Prominent neuronal RNA oxidation has been reported during ageing and presymptomatic stage of ALS, with specific transcripts selectively modified during disease, which may contribute towards selective cellular degeneration. Gene expression changes using microarray technology has been widely used to investigate pathways underlying ageing and neurodegenerative disease. The aim of our study was to investigate the gene expression profile of an oxidised fraction of RNA extracted from the anterior spinal cord of normal mice aged six, twelve, and eighteen months. In data presented here, we identify specific classes of genes to be enriched within the oxidised fraction at each age. Furthermore, genes previously linked to the pathogenesis of ALS and normal ageing, such as those involved in RNA processing and transcriptional regulation, are identified as being differentially oxidised in the anterior spinal cord. The presence and distribution of oxidative damage to nucleic acids within an in vivo model of familial ALS and age-matched controls is demonstrated. The predominance of cytoplasmic 8-hydroxyguanosine reactivity within motor neurons supports previous data of RNA susceptibility to oxidative modification in neurodegenerative disease. Investigation of RNA oxidation in an in vitro model of fALS harbouring G93A and H48Q human SOD1 mutations identified prominent levels of RNA oxidation in comparison to controls, which correlated with a reduction in human SOD1 protein expression within these cells. Subsequent work demonstrated the G93A mutation to be the most susceptible to oxidative stress related cellular decline, in terms of mitochondrial bioenergetics, mitochondrial morphology, and cell viability. The heterogeneity of various SOD1 mutations on cellular function is demonstrated.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Identification Number/EthosID: uk.bl.ethos.605223
Depositing User: Miss Katie Richardson
Date Deposited: 07 May 2014 11:24
Last Modified: 03 Oct 2016 11:16
URI: http://etheses.whiterose.ac.uk/id/eprint/5720

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