PATHOGENESIS OF ALS IN SOD1 TRANSGENIC MICE

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The {long term objective} of this project is to investigate the pathogenesis of ALS using as an animal model transgenic mice which over- express mutant cytosolic superoxide dismutase (SOD) and develop motor neuron disease. The mechanisms whereby mutations initiate motor neuron death are not well defined {One hypothesis currently under investigation is that} abnormal folding of the mutant molecule allows hydrogen peroxide to interact with reduced copper in the active channel, thereby becoming a substrate for a peroxidation reaction. This reaction generates toxic hydroxyl adducts on critical targets. We will test this peroxidation hypothesis by analyzing the effects on the disease phenotype in ALS mice of measures which will reduce peroxidation of hydrogen peroxide. Specific Aim (1) is to generate doubly transgenic mice with both the mutant SOD1 transgene and varying levels of glutathione peroxidase (from none to 10-fold above normal). These experiments will determine whether accelerated clearance of hydrogen peroxide can ameliorate the disease course. Specific Aim (2) will test the possibility that binding and shielding if accessible copper in the mutuant active site will reduce access of hydrogen peroxide to this metal and thereby slow the disease. Copper chelators to be tried include penicillamine and diethyldithiocarbamate. Mice will be monitored for timing of onset of illness and overall survival without and with these interventions. We will also monitor electrophysiological parameters that quantitate motor unit function and activity levels of glutahione peroxidase and {catalase} in brain and spinal cord. We believe these experiments will be significant because they will test both a specific hypothesis regarding the mechanism of neurotoxicity of mutant SOD1 and a potential therapeutic strategy in this lethal disease.