Hydrogen peroxide scavenging rescues frataxin deficiency in a Drosophila model of Friedreich's ataxia.
Friedreich's ataxia (FRDA) is a neurodegenerative disorder arising from a deficit of the mitochondrial iron chaperone, frataxin. Evidence primarily from yeast and mammalian cells is consistent with the hypothesis that a toxic hydroxyl radical generated from hydrogen peroxide (H2O2) via iron-catalyzed Fenton chemistry at least partially underlies the pathology associated with this disease. However, no whole-organism studies have been presented that directly test this hypothesis. We recently developed a Drosophila model that recapitulates the principal hallmarks of FRDA [Anderson PR, Kirby K, Hilliker A, Phillips JP (2005) Hum Mol Genet 14:3397-3405]. Using the Drosophila FRDA model, we now report that ectopic expression of enzymes that scavenge H2O2 suppresses the deleterious phenotypes associated with frataxin deficiency. In contrast, genetic augmentation with enzymes that scavenge superoxide is without effect. Augmentation of endogenous catalase restores the activity of the reactive oxygen species (ROS)-sensitive mitochondrial enzyme, aconitase and enhances resistance to H2O2 exposure, both of which are diminished by frataxin deficiency. Collectively, these data argue that H2O2 is an important pathogenic substrate underlying the phenotypes arising from frataxin deficiency in Drosophila and that interventions that reduce this specific ROS can effectively ameliorate these phenotypes. The therapeutic implications of these findings are clear and we believe warrant immediate clinical investigation.
Anderson
Peter R
PR
Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada N1G 2W1.
Kirby
Kim
K
Orr
William C
WC
Hilliker
Arthur J
AJ
Phillips
John P
JP
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002374:Catalase / Q000737:chemistry* / Q000378:metabolism; D002384:Catalysis; D003720:Densitometry; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics* / Q000502:physiology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005621:Friedreich Ataxia / Q000235:genetics*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007501:Iron / Q000737:chemistry / Q000494:pharmacology; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D008136:Longevity; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D017382:Reactive Oxygen Species; D000096923:Frataxin
D000975:Antioxidants; D002374:Catalase; D016166:Free Radical Scavengers; D006861:Hydrogen Peroxide; D007501:Iron; D033862:Iron-Binding Proteins; D017382:Reactive Oxygen Species; D000096923:Frataxin; C045076:Fenton's reagent