Overexpression of mutant superoxide dismutase 1 causes a motor axonopathy in the zebrafish

Hum Mol Genet. 2007 Oct 1;16(19):2359-65. doi: 10.1093/hmg/ddm193. Epub 2007 Jul 17.


The development of small animal models is of major interest to unravel the pathogenesis and treatment of neurodegenerative diseases, especially because of their potential in large-scale chemical and genetic screening. We have investigated the zebrafish as a model to study amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by the selective loss of motor neurons, caused by mutations in superoxide dismutase 1 (SOD1) in a subset of patients. Overexpression of mutant human SOD1 in zebrafish embryos induced a motor axonopathy that was specific, dose-dependent and found for all mutations studied. Moreover, using this newly established animal model for ALS, we investigated the role of a known modifier in the disease: vascular endothelial growth factor (VEGF). Lowering VEGF induced a more severe phenotype, whereas upregulating VEGF rescued the mutant SOD1 axonopathy. This novel zebrafish model underscores the potential of VEGF for the treatment of ALS and furthermore will permit large-scale genetic and chemical screening to facilitate the identification of new therapeutic targets in motor neuron disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Humans
  • Immunohistochemistry
  • Motor Neuron Disease / enzymology
  • Motor Neuron Disease / genetics*
  • Motor Neuron Disease / pathology
  • Mutation*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Zebrafish


  • RNA, Messenger
  • SOD1 protein, human
  • Vascular Endothelial Growth Factor A
  • Superoxide Dismutase
  • Superoxide Dismutase-1