title: Expression of zinc-deficient human superoxide dismutase in Drosophila neurons produces a locomotor defect linked to mitochondrial dysfunction.
abstract: More than 130 different mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been associated with amyotrophic lateral sclerosis but the mechanism of this toxicity remains controversial. To gain insight into the importance of the zinc site in the pathogenesis of SOD1 in vivo, we generated a Drosophila model with transgenic expression of a zinc-deficient human SOD1. Expression of zinc-deficient SOD1 in Drosophila resulted in a progressive movement defect with associated mitochondrial cristae vacuolization and reductions in adenosine triphosphate (ATP) levels. Furthermore, these flies are sensitized to mitochondrial toxins, paraquat, and zinc. Importantly, we show that the zinc-deficient SOD1-induced motor defect can be ameliorated by supplementing the endogenous fly respiratory chain machinery with the single-subunit NADH-ubiquinone oxidoreductase from yeast (NADH is nicotinamide adenine dinucleotide, reduced form.). These results demonstrate that zinc-deficient SOD1 is neurotoxic in vivo and suggest that mitochondrial dysfunction plays a critical role in this toxicity. The robust behavioral, pathological, and biochemical phenotypes conferred by zinc-deficient SOD1 in Drosophila have general implications for the role of the zinc ion in familial and sporadic amyotrophic lateral sclerosis.
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Sepehr
authors.initials: S
authors.lastname: Bahadorani
authors.forename: Spencer T
authors.initials: ST
authors.lastname: Mukai
authors.forename: Jason
authors.initials: J
authors.lastname: Rabie
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Beckman
authors.forename: John P
authors.initials: JP
authors.lastname: Phillips
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Hilliker
mesh_terms: D000255:Adenosine Triphosphate / Q000172:deficiency; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004330:Drosophila; D005260:Female; D015870:Gene Expression; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D009043:Motor Activity / Q000235:genetics*; D009069:Movement Disorders / Q000235:genetics; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics* / Q000633:toxicity; D014617:Vacuoles / Q000473:pathology; D015032:Zinc / Q000172:deficiency* / Q000502:physiology*
chemical_list: D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D015032:Zinc
keywords: Amyotrophic lateral sclerosis (ALS); Fly; Mitochondria; Ndi1; Paraquat; Respiration; Superoxide dismutase (SOD1)