Human Molecular Genetics Advance Access originally published online on July 17, 2007
Human Molecular Genetics 2007 16(19):2359-2365; doi:10.1093/hmg/ddm193
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Overexpression of mutant superoxide dismutase 1 causes a motor axonopathy in the zebrafish
1 Laboratory of Neurobiology and 2 Department of Neurology, University Hospital Gasthuisberg, K.U. Leuven, Herestraat 49, B-3000 Leuven, Belgium, 3 Department for Transgene Technology and Gene Therapy, VIB, 3000 Leuven, Belgium and 4 The Centre for Transgene Technology and Gene Therapy (CTG), K.U. Leuven, B-3000 Leuven, Belgium
* To whom correspondence should be addressed at: Laboratory of Neurobiology and Department of Neurology, University Hospital Gasthuisberg, K.U. Leuven, Herestraat 49, B-3000 Leuven, Belgium. Tel: +32 16344280; Fax: +32 16344285; Email: robin.lemmens{at}med.kuleuven.be
Received May 25, 2007; Accepted July 14, 2007
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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