title: Pathophysiogical and therapeutic progress in Friedreich ataxia.
abstract: Friedreich ataxia (FRDA) is the most common hereditary autosomal recessive ataxia, but is also a multisystemic condition with frequent presence of cardiomyopathy or diabetes. It has been linked to expansion of a GAA-triplet repeat in the first intron of the FXN gene, leading to a reduced level of frataxin, a mitochondrial protein which, by controlling both iron entry and/or sulfide production, is essential to properly assemble and protect the Fe-S cluster during the initial stage of biogenesis. Several data emphasize the role of oxidative damage in FRDA, but better understanding of pathophysiological consequences of FXN mutations has led to develop animal models. Conditional knockout models recapitulate important features of the human disease but lack the genetic context, GAA repeat expansion-based knock-in and transgenic models carry a GAA repeat expansion but they only show a very mild phenotype. Cells derived from FRDA patients constitute the most relevant frataxin-deficient cell model as they carry the complete frataxin locus together with GAA repeat expansions and regulatory sequences. Induced pluripotent stem cell (iPSC)-derived neurons present a maturation delay and lower mitochondrial membrane potential, while cardiomyocytes exhibit progressive mitochondrial degeneration, with frequent dark mitochondria and proliferation/accumulation of normal mitochondria. Efforts in developing therapeutic strategies can be divided into three categories: iron chelators, antioxidants and/or stimulants of mitochondrial biogenesis, and frataxin level modifiers. A promising therapeutic strategy that is currently the subject of intense research is to directly target the heterochromatin state of the GAA repeat expansion with histone deacytelase inhibitors (HDACi) to restore frataxin levels.
authors.affiliation: Translational medicine and neurogenetics, institut de génétique et de biologie moléculaire et cellulaire (IGBMC), 1, rue Laurent-Fries, BP 10142, 67404 Illkirch cedex, France; Inserm, U596, 1, rue Laurent-Fries, 67400 Illkirch Graffenstaden, France; CNRS, UMR7104, 1, rue Laurent-Fries, 67400 Illkirch Graffenstaden, France; Université de Strasbourg, 4, rue Blaise-Pascal, 67400 Strasbourg, France; Collège de France, chaire de génétique humaine, 1, rue Laurent-Fries, 67400 Illkirch Graffenstaden, France.
authors.forename: H
authors.initials: H
authors.lastname: Puccio
authors.affiliation: Translational medicine and neurogenetics, institut de génétique et de biologie moléculaire et cellulaire (IGBMC), 1, rue Laurent-Fries, BP 10142, 67404 Illkirch cedex, France; Inserm, U596, 1, rue Laurent-Fries, 67400 Illkirch Graffenstaden, France; CNRS, UMR7104, 1, rue Laurent-Fries, 67400 Illkirch Graffenstaden, France; Université de Strasbourg, 4, rue Blaise-Pascal, 67400 Strasbourg, France; Service de neurologie, unité des pathologies du mouvement, hôpital de Hautepierre, hôpital universitaire, 1, place de l'Hôpital, 67000 Strasbourg, France.
authors.forename: M
authors.initials: M
authors.lastname: Anheim
authors.affiliation: Translational medicine and neurogenetics, institut de génétique et de biologie moléculaire et cellulaire (IGBMC), 1, rue Laurent-Fries, BP 10142, 67404 Illkirch cedex, France; Inserm, U596, 1, rue Laurent-Fries, 67400 Illkirch Graffenstaden, France; CNRS, UMR7104, 1, rue Laurent-Fries, 67400 Illkirch Graffenstaden, France; Université de Strasbourg, 4, rue Blaise-Pascal, 67400 Strasbourg, France; Service de neurologie, unité des pathologies du mouvement, hôpital de Hautepierre, hôpital universitaire, 1, place de l'Hôpital, 67000 Strasbourg, France. Electronic address: christine.tranchant@chru-strasbourg.fr.
authors.forename: C
authors.initials: C
authors.lastname: Tranchant
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005621:Friedreich Ataxia / Q000209:etiology* / Q000628:therapy*; D020022:Genetic Predisposition to Disease; D006801:Humans; D033862:Iron-Binding Proteins / Q000502:physiology; D035703:Therapies, Investigational; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D000096923:Frataxin
keywords: Approches thérapeutiques; Ataxie de Friedreich; Frataxine; Friedreich ataxia; Mitochondria; Mitochondries; Physiopathologie; Physiopathology; Therapeutic