Amyotrophic Lateral Sclerosis (ALS) is characterised by motor neuronal degeneration leading to muscular wasting and eventually death. 5% of ALS cases are familial (F ALS) and 20% of these are due to mutations in the gene encoding for copperlzinc superoxide dismutase-l (SOD1). Mice overexpressing human mutant SODl develop a neurodegenerative condition closely resembling ALS. Beyond increasing age, male gender and family history of ALS, there are no other validated risk factors. However, recently, association between intense physical activity and ALS has been proposed by epidemiological studies. In the first part of this thesis, the response of motor neurones to the stress caused by the presence of the mutant human SOD 1 in the mouse model of F ALS was investigated. In the second part, the genes and pathways involved in the physiological response to the stress caused by voluntary exercise in motor neurones were identified. The final section of this thesis investigated whether single nucleotide polymorphisms (SNPs) in key genes involved in the response to exercise were associated with the pathophysiology of ALS. Microarray analysis of motor neurones isolated using laser capture microdissection from the lumbar spinal cord of G93A-SOD 1 mice and their littermates at different stages of disease has identified several potential targets for drug therapy, especially at the presymptomatic stage. Applying the same techniques, the transcription profile of motor neurones isolated from the lumbar spinal cord of exercised and sedentary mice was analysed as well as gastrocnemius muscles. Motor neurones showed transcriptional changes involved in neurotrophic factor signalling, electrophysiological changes and synaptic reorganization, while gastrocnemius muscle revealed mcreases in transcripts responsible for neovascularisation and myogenesis. The comparison between the two studies reveals that, although the pathways activated in motor neurones in response to the two stresses are different, the physiological response to exercise requires production of neurotrophic factors and activation of pathways that have been shown to be implicated in the pathology of ALS. In particular, VEGF receptor 2 (KDR) was upregulated in response to exercise. In order to investigate the hypothesis that genetic susceptibility could be implicated in a failure to mount the physiological response to exercise, non-synonymous SNPs in KDR were screened in sporadic ALS cases and controls. Although the screening did not reveal any positive associations, the present study provides additional candidate genes that might confer a genetic susceptibility to ALS in response to intense physical activity.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:505434 |
| Date | January 2009 |
| Creators | Ferraiuolo, Laura |
| Publisher | University of Sheffield |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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