title: A genetic model of amyotrophic lateral sclerosis in zebrafish displays phenotypic hallmarks of motoneuron disease.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that, for approximately 80% of patients, is fatal within five years of diagnosis. To better understand ALS, animal models have been essential; however, only rodent models of ALS exhibit the major hallmarks of the disease. Here, we report the generation of transgenic zebrafish overexpressing mutant Sod1. The construct used to generate these lines contained the zebrafish sod1 gene and approximately 16 kb of flanking sequences. We generated lines expressing the G93R mutation, as well as lines expressing wild-type Sod1. Focusing on two G93R lines, we found that they displayed the major phenotypes of ALS. Changes at the neuromuscular junction were observed at larval and adult stages. In adulthood the G93R mutants exhibited decreased endurance in a swim tunnel test. An analysis of muscle revealed normal muscle force, however, at the end stage the fish exhibited motoneuron loss, muscle atrophy, paralysis and premature death. These phenotypes were more severe in lines expressing higher levels of mutant Sod1 and were absent in lines overexpressing wild-type Sod1. Thus, we have generated a vertebrate model of ALS to complement existing mammal models.
authors.affiliation: Center for Molecular Neurobiology and Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA. t.ramesh@sheffield.ac.uk
authors.forename: Tennore
authors.initials: T
authors.lastname: Ramesh
authors.forename: Alison N
authors.initials: AN
authors.lastname: Lyon
authors.forename: Ricardo H
authors.initials: RH
authors.lastname: Pineda
authors.forename: Chunping
authors.initials: C
authors.lastname: Wang
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Canan
authors.forename: Arthur H M
authors.initials: AH
authors.lastname: Burghes
authors.forename: Christine E
authors.initials: CE
authors.lastname: Beattie
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D001284:Atrophy; D004195:Disease Models, Animal; D007814:Larva / Q000378:metabolism; D008957:Models, Genetic; D016472:Motor Neuron Disease / Q000235:genetics* / Q000473:pathology*; D009046:Motor Neurons / Q000473:pathology; D009119:Muscle Contraction; D009132:Muscles / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000473:pathology; D010641:Phenotype; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis; D015027:Zebrafish / Q000235:genetics*
chemical_list: D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1