Expression of zinc-deficient human superoxide dismutase in Drosophila neurons produces a locomotor defect linked to mitochondrial dysfunction
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Updated: May 12, 2026
Toxicity Study of Zinc Oxide Nanoparticles in Cell Culture and in Drosophila melanogaster
Published on: September 19, 2019
Sepehr Bahadorani1, Spencer T Mukai, Jason Rabie
1Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
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.
Insights
Zinc-deficient SOD1 causes neurotoxicity and mitochondrial dysfunction in a Drosophila model of amyotrophic lateral sclerosis. Restoring mitochondrial function ameliorates motor defects, highlighting the role of zinc in ALS pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Over 130 mutations in the copper-zinc superoxide dismutase (SOD1) gene are linked to amyotrophic lateral sclerosis (ALS).
- The precise mechanism of SOD1-associated neurotoxicity, particularly the role of its zinc site, remains unclear.
- Understanding SOD1's role in ALS pathogenesis is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the in vivo role of the zinc site in SOD1-induced neurotoxicity.
- To establish a Drosophila model for studying zinc-deficient SOD1 in amyotrophic lateral sclerosis.
- To elucidate the contribution of mitochondrial dysfunction to SOD1-related pathogenesis.
Main Methods:
- Generated a Drosophila model expressing zinc-deficient human SOD1.
- Assessed behavioral phenotypes, including motor defects.
- Examined mitochondrial structure (cristae vacuolization) and adenosine triphosphate (ATP) levels.
- Tested sensitivity to mitochondrial toxins (paraquat, zinc).
- Investigated therapeutic potential by supplementing with yeast NADH-ubiquinone oxidoreductase.
Main Results:
- Transgenic expression of zinc-deficient SOD1 induced progressive motor deficits in Drosophila.
- Observed mitochondrial cristae vacuolization and reduced ATP levels in affected flies.
- Flies expressing zinc-deficient SOD1 showed increased sensitivity to paraquat and zinc.
- Supplementation with yeast NADH-ubiquinone oxidoreductase ameliorated the motor defects.
Conclusions:
- Zinc-deficient SOD1 is neurotoxic in vivo, leading to motor impairments and mitochondrial dysfunction.
- Mitochondrial dysfunction is a critical component of zinc-deficient SOD1 toxicity.
- These findings underscore the importance of the zinc ion in both familial and sporadic amyotrophic lateral sclerosis.
