title: Overexpression of mutant superoxide dismutase 1 causes a motor axonopathy in the zebrafish.
abstract: 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.
authors.affiliation: Department of Neurology, University Hospital Gasthuisberg, K.U. Leuven, Belgium. robin.lemmens@med.kuleuven.be
authors.forename: Robin
authors.initials: R
authors.lastname: Lemmens
authors.forename: Annelies
authors.initials: A
authors.lastname: Van Hoecke
authors.forename: Nicole
authors.initials: N
authors.lastname: Hersmus
authors.forename: Veerle
authors.initials: V
authors.lastname: Geelen
authors.forename: Isabel
authors.initials: I
authors.lastname: D'Hollander
authors.forename: Vincent
authors.initials: V
authors.lastname: Thijs
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006801:Humans; D007150:Immunohistochemistry; D016472:Motor Neuron Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
chemical_list: D012333:RNA, Messenger; C000606290:SOD1 protein, human; D042461:Vascular Endothelial Growth Factor A; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1