title: A drosophila model for amyotrophic lateral sclerosis reveals motor neuron damage by human SOD1.
abstract: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that leads to loss of motor function and early death. About 5% of cases are inherited, with the majority of identified linkages in the gene encoding copper, zinc-superoxide dismutase (SOD1). Strong evidence indicates that the SOD1 mutations confer dominant toxicity on the protein. To provide new insight into mechanisms of ALS, we have generated and characterized a model for familial ALS in Drosophila with transgenic expression of human SOD1. Expression of wild type or disease-linked (A4V, G85R) mutants of human SOD1 selectively in motor neurons induced progressive climbing deficits. These effects were accompanied by defective neural circuit electrophysiology, focal accumulation of human SOD1 protein in motor neurons, and a stress response in surrounding glia. However, toxicity was not associated with oligomerization of SOD1 and did not lead to neuronal loss. These studies uncover cell-autonomous injury by SOD1 to motor neurons in vivo, as well as non-autonomous effects on glia, and provide the foundation for new insight into injury and protection of motor neurons in ALS.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Watson
authors.forename: Robert D
authors.initials: RD
authors.lastname: Lagow
authors.forename: Kexiang
authors.initials: K
authors.lastname: Xu
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D004594:Electrophysiology; D005799:Genes, Dominant; D006801:Humans; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D020125:Mutation, Missense; D009457:Neuroglia / Q000201:enzymology / Q000473:pathology; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D019076:Transgenes
chemical_list: C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1