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.
Phenotype correlation and intergenerational dynamics of the Friedreich ataxia GAA trinucleotide repeat
The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis
Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits
Friedreich ataxia mouse models with progressive cerebellar and sensory ataxia reveal autophagic neurodegeneration in dorsal root ganglia
GAA repeat expansion mutation mouse models of Friedreich ataxia exhibit oxidative stress leading to progressive neuronal and cardiac pathology
The GAA triplet-repeat is unstable in the context of the human FXN locus and displays age-dependent expansions in cerebellum and DRG in a transgenic mouse model
Somatic instability of the expanded GAA triplet-repeat sequence in Friedreich ataxia progresses throughout life
Frataxin deficiency causes upregulation of mitochondrial Lon and ClpP proteases and severe loss of mitochondrial Fe-S proteins
The first cellular models based on frataxin missense mutations that reproduce spontaneously the defects associated with Friedreich ataxia
Red blood cell generation from human induced pluripotent stem cells: perspectives for transfusion medicine
Huntington's and myotonic dystrophy hESCs: down-regulated trinucleotide repeat instability and mismatch repair machinery expression upon differentiation
Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA⋅TTC triplet repeat instability
Blood cells from Friedreich ataxia patients harbor frataxin deficiency without a loss of mitochondrial function
Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex.
The mismatch repair system protects against intergenerational GAA repeat instability in a Friedreich ataxia mouse model
Understanding the genetic and molecular pathogenesis of Friedreich's ataxia through animal and cellular models
Role of mismatch repair enzymes in GAA·TTC triplet-repeat expansion in Friedreich ataxia induced pluripotent stem cells.
Induced pluripotent stem cells from friedreich ataxia patients fail to upregulate frataxin during in vitro differentiation to peripheral sensory neurons
Genetic variations creating microRNA target sites in the FXN 3'-UTR affect frataxin expression in Friedreich ataxia
Generation and characterisation of Friedreich ataxia YG8R mouse fibroblast and neural stem cell models
Base excision repair of chemotherapeutically-induced alkylated DNA damage predominantly causes contractions of expanded GAA repeats associated with Friedreich's ataxia
Human stem cell models of neurodegeneration: a novel approach to study mechanisms of disease development
Frataxin silencing inactivates mitochondrial Complex I in NSC34 motoneuronal cells and alters glutathione homeostasis
ONSL and OSKM cocktails act synergistically in reprogramming human somatic cells into induced pluripotent stem cells.
Modeling of Friedreich ataxia-related iron overloading cardiomyopathy using patient-specific-induced pluripotent stem cells
Functional characterization of Friedreich ataxia iPS-derived neuronal progenitors and their integration in the adult brain
The potential of induced pluripotent stem cells in models of neurological disorders: implications on future therapy
Revisiting Mitochondrial Function and Metabolism in Pluripotent Stem Cells: Where Do We Stand in Neurological Diseases?
Barth Syndrome: From Mitochondrial Dysfunctions Associated with Aberrant Production of Reactive Oxygen Species to Pluripotent Stem Cell Studies
Cardiomyopathy in a dish: using human inducible pluripotent stem cells to model inherited cardiomyopathies
Neurodegenerative diseases in a dish: the promise of iPSC technology in disease modeling and therapeutic discovery
Stem cells on the brain: modeling neurodevelopmental and neurodegenerative diseases using human induced pluripotent stem cells
Mitochondrial dysfunction induced by frataxin deficiency is associated with cellular senescence and abnormal calcium metabolism
Utility of Induced Pluripotent Stem Cells for the Study and Treatment of Genetic Diseases: Focus on Childhood Neurological Disorders
Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming
Abnormal base excision repair at trinucleotide repeats associated with diseases: a tissue-selective mechanism
Epigenetic alterations mediate iPSC-induced normalization of DNA repair gene expression and TNR stability in Huntington's disease cells.
Finding the rhythm of sudden cardiac death: new opportunities using induced pluripotent stem cell-derived cardiomyocytes
Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures
GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich ataxia cellular models
Correlation between frataxin expression and contractility revealed by in vitro Friedreich's ataxia cardiac tissue models engineered from human pluripotent stem cells
Length-dependent CTG·CAG triplet-repeat expansion in myotonic dystrophy patient-derived induced pluripotent stem cells
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