ZFIN ID: ZDB-PUB-131108-19
A new zebrafish model of SOD1 ALS produced by TILLING replicates key features of the disease and represents a tool for in vivo therapeutic screening
Da Costa, M.M., Allen, C.E., Higginbottom, A., Ramesh, T., Shaw, P.J., and McDermott, C.J.
Date: 2014
Source: Disease models & mechanisms   7(1): 73-81 (Journal)
Registered Authors: Allen, Claire, Da Costa, Marc
Keywords: MND, ALS, SOD1, Zebrafish
MeSH Terms:
  • Alleles
  • Amyotrophic Lateral Sclerosis/genetics*
  • Animals
  • Animals, Genetically Modified
  • Antioxidants/chemistry
  • Disease Models, Animal*
  • Genetic Predisposition to Disease
  • Homozygote
  • Humans
  • Male
  • Movement
  • Mutagenesis
  • Mutation
  • Neuromuscular Junction/metabolism
  • Neurons/physiology
  • Neuroprotective Agents/chemistry
  • Oxidative Stress
  • Phenotype
  • Superoxide Dismutase/genetics*
  • Zebrafish
PubMed: 24092880 Full text @ Dis. Model. Mech.

Mutations in the superoxide dismutase gene (SOD1) are one cause of familial amyotrophic lateral sclerosis [ALS; also known as motor neuron disease (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 transgenic murine models of the disease, which overexpress mutant SOD1, have so far been ineffective in the identification of new therapies beneficial in the human disease. Because the human and the zebrafish (Danio rerio) SOD1 protein share 76% identity, 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 (NMJ) 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, as occurs in humans with ALS. The T70I sod1 zebrafish demonstrates key features of ALS: an early NMJ phenotype, susceptibility to oxidative stress and an adult-onset motor neuron disease 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.