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Title: Investigating new mouse models of amyotrophic lateral sclerosis
Author: McGoldrick, P.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Amyotrophic Lateral Sclerosis (ALS) is a progressive fatal neurodegenerative disease characterised by motor neuron degeneration and muscle denervation, atrophy and eventual paralysis. Approximately 10% of ALS cases are familial, caused by mutations in a range of genes including superoxide dismutase 1 (SOD1), TDP-43 (TARDBP) and fused-in-sarcoma (FUS), although the most common genetic cause of ALS is now thought to be a hexanucleotide repeat in C9ORF72. Mouse models of ALS, most commonly created by overexpressing wildtype or disease-causing mutant human proteins, have been critical for our understanding of ALS pathogenesis. In this Thesis I investigated a number of new mouse models that express ALS-causing mutations including mutant mice created through N-ethyl-N-nitrosourea (ENU) mutagenesis, which induces random point mutations in the mouse genome, resulting in expression of the mutant proteins at physiological levels, as well as a new transgenic mouse which over-expresses wildtype human FUS. In the first experiments, a mutant mouse carrying a D83G mutation in mouse Sod1, analogous to a pathogenic human mutation, was examined. Sod1D83G/D83G mice show motor neuron degeneration and axonopathy. Examination of cultured primary embryonic motor neurons revealed that Sod1D83G/D83G motor neurons have a reduced viability, a reduction in neurite outgrowth and significant deficits in mitochondrial function. In the second set of experiments, four different mice with ENU-induced mutations in TDP-43 were examined. These mice did not show any signs of neuromuscular dysfunction in vivo, or signs of pathology in vitro, assessed by neurite outgrowth and stress granule formation. Furthermore, crossing TDP-43 mutant mice with SOD1G93A transgenic mice did not modify disease progression. In the final set of experiments, transgenic mice overexpressing wildtype human FUS were investigated. In vivo assessment of neuromuscular function in homozygote mice at 10 weeks of age revealed significant pathological changes in muscle function and motor unit survival. These results characterise a novel ENU-induced mouse model of mutant SOD1-induced ALS and a new transgenic mouse model in which overexpression of wildtype human FUS causes a severe motor phenotype. However, ENU-induced mutations in mouse TDP-43 do not result in any overt motor phenotype.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available