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An investigation of the behaviour of superoxide dismutase 1 in in-vitro models of motor neuron disease

Stevens, J.C.; (2009) An investigation of the behaviour of superoxide dismutase 1 in in-vitro models of motor neuron disease. Doctoral thesis, UCL (University College London).

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Abstract

Motor neuron disease is an incurable neurodegenerative condition. A proportion of motor neuron disease is inherited in autosomal dominant manner, of which approximately 10% is due to mutations in the enzyme superoxide dismutase 1 (SOD1). The mechanism by which mutant SOD1 selectively kills motor neurons is not understood. Motor neuron disease due to mutant SOD1 has been modelled by the SOD1 transgenic mouse which possesses a SOD^{G93A} transgene array. This mouse develops progressive motor neuron loss, resulting in premature death. The Legs at odd angles (Loa) mouse, which has a missense mutation in the gene encoding cytoplasmic dunein, develops progressive – wild-type, Loa/+, SOD1 ^{G93A} and Loa/SOD1^{G93A}. Surprisingly, Loa/SOD1^{G93A} mice survive significantly longer than their SOD1^{G93A} littermates, thus the presence of a mutation in dynein reduces the toxic effect of mutant SOD1. To gain further understanding of how mutant SOD1 kills motor neurons, the behaviour of mutant SOD1 between neurons of these genotypes was compared. Differences in behaviour of mutant SOD1 between these genotypes may correlate with the observed differences in survival and thereby suggest toxic mechanisms. Methods of tagging SOD1 for live cell imaging were assessed and strategies of transfecting cultured motor neurons with tagged SOD1 evaluated. Lentiviral vectors were used to transduce cultured motor neurons with tagged SOD1. Methods of assessing anterograde axonal transport were evaluated. The localisation and movement characteristics of wild-type and mutant SOD1 were evaluated in wild-type motor neurons. No statistically significant differences were found. The localisation and movement characteristics of mutant SOD1 was evaluated in motor neurons of genotypes wild-type, Loa/+, SOD1^{G93A} and Loa/ SOD1^{G93A}. No statistically significant differences were found. Thus the behaviour of the toxic moiety, mutant SOD1, was not demonstrated to be different between neurons with different survival characteristics.

Type:Thesis (Doctoral)
Title:An investigation of the behaviour of superoxide dismutase 1 in in-vitro models of motor neuron disease
Language:English
Additional information:Authorisation for digitisation not received. Abstract contains LATEX text. Please see thesis for rendered formulae and equations
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Neurodegenerative Diseases

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