title: Deferiprone and idebenone rescue frataxin depletion phenotypes in a Drosophila model of Friedreich's ataxia.
abstract: Friedreich's ataxia (FRDA), the most common inherited ataxia, is a neurodegenerative disease caused by a reduction in the levels of the mitochondrial protein frataxin, the function of which remains a controversial matter. Several therapeutic approaches are being developed to increase frataxin expression and reduce the intramitochondrial iron aggregates and oxidative damage found in this disease. In this study, we tested separately the response of a Drosophila RNAi model of FRDA (Llorens et al., 2007) to treatment with the iron chelator deferiprone (DFP) and the antioxidant idebenone (IDE), which are both in clinical trials. The FRDA flies have a shortened life span and impaired motor coordination, and these phenotypes are more pronounced in oxidative stress conditions. In addition, under hyperoxia, the activity of the mitochondrial enzyme aconitase is strongly reduced in the FRDA flies. This study reports that DFP and IDE improve the life span and motor ability of frataxin-depleted flies. We show that DFP eliminates the excess of labile iron in the mitochondria and thus prevents the toxicity induced by iron accumulation. IDE treatment rescues aconitase activity in hyperoxic conditions. These results validate the use of our Drosophila model of FRDA to screen for therapeutic molecules to treat this disease.
authors.affiliation: Departament de Genètica, Universitat de València, Burjassot, Valencia, Spain.
authors.forename: Sirena
authors.initials: S
authors.lastname: Soriano
authors.forename: José V
authors.initials: JV
authors.lastname: Llorens
authors.forename: Laura
authors.initials: L
authors.lastname: Blanco-Sobero
authors.forename: Lucía
authors.initials: L
authors.lastname: Gutiérrez
authors.forename: Pablo
authors.initials: P
authors.lastname: Calap-Quintana
authors.forename: M Puerto
authors.initials: MP
authors.lastname: Morales
authors.forename: M Dolores
authors.initials: MD
authors.lastname: Moltó
authors.forename: M José
authors.initials: MJ
authors.lastname: Martínez-Sebastián
mesh_terms: D000154:Aconitate Hydratase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000077543:Deferiprone; D004195:Disease Models, Animal; D004330:Drosophila; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018496:Hyperoxia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D011728:Pyridones / Q000494:pharmacology*; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000096923:Frataxin
chemical_list: D000154:Aconitate Hydratase; D000975:Antioxidants; D000077543:Deferiprone; D007501:Iron; D033862:Iron-Binding Proteins; D011728:Pyridones; D014451:Ubiquinone; D000096923:Frataxin; C036619:idebenone