Expression of zinc-deficient human superoxide dismutase in Drosophila neurons produces a locomotor defect linked to mitochondrial dysfunction

Neurobiol Aging. 2013 Oct;34(10):2322-30. doi: 10.1016/j.neurobiolaging.2013.03.024. Epub 2013 Apr 17.

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.

Keywords: Amyotrophic lateral sclerosis (ALS); Fly; Mitochondria; Ndi1; Paraquat; Respiration; Superoxide dismutase (SOD1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / deficiency
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Disease Models, Animal
  • Disease Progression
  • Drosophila
  • Female
  • Gene Expression
  • Male
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mitochondria / ultrastructure
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / pathology
  • Motor Activity / genetics*
  • Movement Disorders / genetics
  • Mutation
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / toxicity
  • Vacuoles / pathology
  • Zinc / deficiency*
  • Zinc / physiology*

Substances

  • Adenosine Triphosphate
  • Superoxide Dismutase
  • Zinc