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

Sepehr Bahadorani, Spencer T. Mukai, Jason Rabie, Joseph S. Beckman, John P. Phillips, Arthur J. Hilliker

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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 invivo, 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 invivo 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.

Original languageEnglish (US)
Pages (from-to)2322-2330
Number of pages9
JournalNeurobiology of Aging
Volume34
Issue number10
DOIs
StatePublished - Oct 2013
Externally publishedYes

Keywords

  • Amyotrophic lateral sclerosis (ALS)
  • Fly
  • Mitochondria
  • Ndi1
  • Paraquat
  • Respiration
  • Superoxide dismutase (SOD1)

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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