Bunton-Stasyshyn, RKA; (2014) The role of wild-type SOD1 in SOD1 mouse models of ALS. Doctoral thesis , UCL (University College London).

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Abstract

Amyotrophic lateral sclerosis (ALS) is the most common form of adult onset motor neuron disease. It is primarily sporadic, however a proportion of cases are inherited and of these ~10% are caused by mutations in the gene SOD1. Recent research points to a possible role for wild-type (WT) SOD1 in ALS. This thesis addresses questions about the role of WT-SOD1 in ALS in the context of mouse models of ALS. The first set of experiments address whether pathogenically misfolded SOD1 can act in a “prion-like” way, recruiting WT-SOD1 into a pathogenic conformation in vivo. SOD1 transgenic mice were intracerebrally inoculated with homogenates prepared from central nervous system tissue from mouse or human which contains pathogenic SOD1. Pathology was assessed at a number of post-inoculation time-points to determine whether misfolding of transgenically expressed SOD1G93A was increased, or misfolding of transgenically expressed WT-SOD1 was induced. The project described above used transgenic mice bred onto an endogenous Sod1 null background because evidence from the prion field suggests that the endogenous protein could interfere with transmission of human misfolded SOD1. The effect of endogenous SOD1 on the disease phenotype of SOD1G93A transgenic mice was not known, therefore mice of 4 genotypes were examined: WT, Sod1-/-, Tg SOD1G93A and Sod1-/-;Tg SOD1G93A. Grip-strength and survival was measured. Muscle and spinal cord pathology were also examined at two time-points. Finally, a project to create a new mouse model of SOD1-fALS is described; a genomically humanised mouse with an inducible LoxP-Cre mutant/WT allele. Cloning of the targeting constructs was carried out using a combination of traditional restriction endonuclease cloning and recombineering. Finalising the constructs and embryonic stem cell targeting is underway. This work aims to increase our understanding of how WT-SOD1 may be involved in both familial and sporadic ALS and provide more accurate models SOD1-fALS.

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