title: A Yeast/Drosophila Screen to Identify New Compounds Overcoming Frataxin Deficiency.
abstract: Friedreich's ataxia (FA) is a rare neurodegenerative disease which is very debilitating for the patients who progressively lose their autonomy. The lack of efficient therapeutic treatment of the disease strongly argues for urgent need to search for new active compounds that may stop the progression of the disease or prevent the appearance of the symptoms when the genetic defect is diagnosed early enough. In the present study, we used a yeast strain with a deletion of the frataxin homologue gene as a model of FA cells in a primary screen of two chemical libraries, a fraction of the French National Chemical Library (5500 compounds) and the Prestwick collection (880 compounds). We ran a secondary screen on Drosophila melanogaster flies expressing reduced levels of frataxin during larval development. Half of the compounds selected in yeast appeared to be active in flies in this developmental paradigm, and one of the two compounds with highest activities in this assay partially rescued the heart dilatation phenotype resulting from heart specific depletion of frataxin. The unique complementarity of these two frataxin-deficient models, unicellular and multicellular, appears to be very efficient to select new compounds with improved selectivity, bringing significant perspectives towards improvements in FA therapy.
authors.affiliation: "Mitochondries, Métaux et Stress Oxydant", Institut Jacques Monod, UMR7592 CNRS-Université Paris Diderot, Sorbonne Paris Cité, 15 rue Hélène Brion, 75205 Paris Cedex 13, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Seguin
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR8251 CNRS-Université Paris Diderot, Sorbonne Paris Cité, 4 rue M. A. Lagroua Weill Halle, 75205 Paris Cedex 13, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Monnier
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR8251 CNRS-Université Paris Diderot, Sorbonne Paris Cité, 4 rue M. A. Lagroua Weill Halle, 75205 Paris Cedex 13, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Palandri
authors.affiliation: Laboratoire d'Innovation Thérapeutique, UMR7200 CNRS-Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, BP 60024, 67401 Illkirch Cedex, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bihel
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR8251 CNRS-Université Paris Diderot, Sorbonne Paris Cité, 4 rue M. A. Lagroua Weill Halle, 75205 Paris Cedex 13, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Rera
authors.affiliation: Laboratoire d'Innovation Thérapeutique, UMR7200 CNRS-Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, BP 60024, 67401 Illkirch Cedex, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: "Mitochondries, Métaux et Stress Oxydant", Institut Jacques Monod, UMR7592 CNRS-Université Paris Diderot, Sorbonne Paris Cité, 15 rue Hélène Brion, 75205 Paris Cedex 13, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Camadro
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR8251 CNRS-Université Paris Diderot, Sorbonne Paris Cité, 4 rue M. A. Lagroua Weill Halle, 75205 Paris Cedex 13, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tricoire
authors.affiliation: "Mitochondries, Métaux et Stress Oxydant", Institut Jacques Monod, UMR7592 CNRS-Université Paris Diderot, Sorbonne Paris Cité, 15 rue Hélène Brion, 75205 Paris Cedex 13, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lesuisse
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D007814:Larva / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D018715:Microscopy, Video; D011887:Raffinose / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D000096923:Frataxin
chemical_list: D029721:Drosophila Proteins; D033862:Iron-Binding Proteins; D011887:Raffinose; D029701:Saccharomyces cerevisiae Proteins; D054852:Small Molecule Libraries; D000096923:Frataxin