Mutations in the superoxide dismutase gene (SOD1) cause familial amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) in humans. ALS is a relentlessly progressive neurodegenerative disease and to date there are no neuroprotective therapies with significant impact on the disease course. Current over-expressing mutant SOD1 transgenic murine models have so far been ineffective in the identification of new therapies beneficial in the human disease. As the human and the zebrafish (Danio rerio) SOD1 protein share 76% homology, TILLING (Targeting Induced Local Lesions IN Genomes) was carried out in collaboration with the Sanger Institute in order to identify mutations in the zebrafish sod1 gene. A T70I mutant zebrafish line was characterised using oxidative stress assays, neuromuscular junction analysis and motor function studies. The T70I sod1 zebrafish model offers the advantage over current murine models, of expressing the mutant Sod1 protein at a physiological level, akin to human ALS patients. The T70I sod1 zebrafish demonstrate key features of ALS; an early NMJ phenotype; a susceptibility to oxidative stress, and an adult onset motor phenotype. We have demonstrated that the susceptibility of T70I sod1 embryos to oxidative stress can be used in a drug screening assay, to identify compounds that merit further investigation as potential therapies for ALS.
- Received February 18, 2013.
- Accepted September 29, 2013.
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