title: Neurons and cardiomyocytes derived from induced pluripotent stem cells as a model for mitochondrial defects in Friedreich's ataxia.
abstract: Friedreich's ataxia (FRDA) is a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy. FRDA is due to expanded GAA repeats within the first intron of the gene encoding frataxin, a conserved mitochondrial protein involved in iron-sulphur cluster biosynthesis. This mutation leads to partial gene silencing and substantial reduction of the frataxin level. To overcome limitations of current cellular models of FRDA, we derived induced pluripotent stem cells (iPSCs) from two FRDA patients and successfully differentiated them into neurons and cardiomyocytes, two affected cell types in FRDA. All FRDA iPSC lines displayed expanded GAA alleles prone to high instability and decreased levels of frataxin, but no biochemical phenotype was observed. Interestingly, both FRDA iPSC-derived neurons and cardiomyocytes exhibited signs of impaired mitochondrial function, with decreased mitochondrial membrane potential and progressive mitochondrial degeneration, respectively. Our data show for the first time that FRDA iPSCs and their neuronal and cardiac derivatives represent promising models for the study of mitochondrial damage and GAA expansion instability in FRDA.
authors.affiliation: Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Hick
authors.forename: Marie
authors.initials: M
authors.lastname: Wattenhofer-Donzé
authors.forename: Satyan
authors.initials: S
authors.lastname: Chintawar
authors.forename: Philippe
authors.initials: P
authors.lastname: Tropel
authors.forename: Jodie P
authors.initials: JP
authors.lastname: Simard
authors.forename: Nadège
authors.initials: N
authors.lastname: Vaucamps
authors.forename: David
authors.initials: D
authors.lastname: Gall
authors.forename: Laurie
authors.initials: L
authors.lastname: Lambot
authors.forename: Cécile
authors.initials: C
authors.lastname: André
authors.forename: Laurence
authors.initials: L
authors.lastname: Reutenauer
authors.forename: Myriam
authors.initials: M
authors.lastname: Rai
authors.forename: Marius
authors.initials: M
authors.lastname: Teletin
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.forename: Serge N
authors.initials: SN
authors.lastname: Schiffmann
authors.forename: Stéphane
authors.initials: S
authors.lastname: Viville
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Pearson
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
authors.forename: Hélène
authors.initials: H
authors.lastname: Puccio
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D053843:DNA Mismatch Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology; D005621:Friedreich Ataxia / Q000473:pathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000473:pathology*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D010641:Phenotype; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D045643:DNA Repair Enzymes