Neurons and cardiomyocytes derived from induced pluripotent stem cells as a model for mitochondrial defects in Friedreich's ataxia

Hick, Aurore; Wattenhofer‐Donzé, Marie; Chintawar, Satyan; Tropel, Philippe; Simard, Jodie P.; Vaucamps, Nadège; Gall, David; Lambot, Laurie; André, Cécile; Reutenauer, Laurence; Rai, Myriam; Teletin, Marius; Messaddeq, Nadia; Schiffmann, Serge N.; Viville, Stéphane; Pearson, Christopher E.; Pandolfo, Massimo; Puccio, Hélène

doi:10.1242/dmm.010900

Cited by 135 publications

(154 citation statements)

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“…This phenomenon has been observed in all cell lines and somatic tissues derived from FRDA patients [18]. In addition, we and others demonstrated that reprogramming FRDA primary fibroblasts into iPSCs using standard conditions of retrovirus-mediated delivery of the reprogramming factors Oct4, Sox2, Klf4, and c-Myc (OSKM) [38,39] does not affect the epigenetic status or transcriptional repression of the FXN locus containing expanded GAA repeats [32,40].…”

Section: Expansion Of Gaa Repeats Silences Expression Of the Fxn Genementioning

confidence: 52%

Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming

Polak

Butler

et al. 2016

Stem Cells and Development

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Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia. This severe neurodegenerative disease is caused by an expansion of guanine-adenine-adenine (GAA) repeats located in the first intron of the frataxin (FXN) gene, which represses its transcription. Although transcriptional silencing is associated with heterochromatin-like changes in the vicinity of the expanded GAAs, the exact mechanism and pathways involved in transcriptional inhibition are largely unknown. As major remodeling of the epigenome is associated with somatic cell reprogramming, modulating chromatin modification pathways during the cellular transition from a somatic to a pluripotent state is likely to generate permanent changes to the epigenetic landscape. We hypothesize that the epigenetic modifications in the vicinity of the GAA repeats can be reversed by pharmacological modulation during somatic cell reprogramming. We reprogrammed FRDA fibroblasts into induced pluripotent stem cells (iPSCs) in the presence of various small molecules that target DNA methylation and histone acetylation and methylation. Treatment of FRDA iPSCs with two compounds, sodium butyrate (NaB) and Parnate, led to an increase in FXN expression and correction of repressive marks at the FXN locus, which persisted for several passages. However, prolonged culture of the epigenetically modified FRDA iPSCs led to progressive expansions of the GAA repeats and a corresponding decrease in FXN expression. Furthermore, we uncovered that differentiation of these iPSCs into neurons also results in resilencing of the FXN gene. Taken together, these results demonstrate that transcriptional repression caused by long GAA repeat tracts can be partially or transiently reversed by altering particular epigenetic modifications, thus revealing possibilities for detailed analyses of silencing mechanism and development of new therapeutic approaches for FRDA.

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Section: Expansion Of Gaa Repeats Silences Expression Of the Fxn Genementioning

confidence: 52%

Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming

Polak

Butler

et al. 2016

Stem Cells and Development

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“…However, associated symptoms and complications can be treated [1]. Neurons and cardiomyocytes are the two affected cell types in FRDA [8]. As human stem cells have ability to migrate and home to the injury site [15], we could assume that hESCs might have also migrated to the affected brain and differentiated into neurons and cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Lack of FXN causes iron overloading and increase free-radical production [7] that triggers a series of metabolic derangements [4]. The underlying molecular mechanisms for instability in GAA repeat are currently unknown [8].…”

Section: Introductionmentioning

confidence: 99%

A novel approach of human embryonic stem cells therapy in treatment of Friedrich's Ataxia

Shroff¹

2015

IJCRI

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International Journal of Case Reports and Images (IJCRI) is an international, peer reviewed, monthly, open access, online journal, publishing high-quality, articles in all areas of basic medical sciences and clinical specialties.Aim of IJCRI is to encourage the publication of new information by providing a platform for reporting of unique, unusual and rare cases which enhance understanding of disease process, its diagnosis, management and clinico-pathologic correlations. IJCRI publishes

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“…None of these studies have yet successfully recapitulated the specific cerebellar neuronal dysfunction and degeneration known to characterize these conditions. In human iPSC-based studies of FRDA, which is caused by an intronic repeat expansion in the FXN gene encoding Frataxin, disease-relevant phenotypes such as reduced Frataxin mRNA and protein levels as well as mitochondrial defects were observed in cardiomyocytes and peripheral sensory neurons, two of the affected cell types in FRDA [33][34][35][36] . In the case of A-T, chromosomal instability and cell cycle checkpoint defects, resulting from mutations in the ATM gene encoding ataxia-telangiectasia mutated (ATM) protein, have been found to reduce the efficiency of the reprogramming of A-T iPSCs 37 .…”

Section: Disease Modelling Of Cerebellar Ataxiasmentioning

confidence: 99%

Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

Wong

Watson

Becker

2017

J Neurol Neuromedicine

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The cerebellar ataxias are a group of incurable brain disorders that are caused primarily by the progressive dysfunction and degeneration of cerebellar Purkinje cells. The lack of reliable disease models for the heterogeneous ataxias has hindered the understanding of the underlying pathogenic mechanisms as well as the development of effective therapies for these devastating diseases. Recent advances in the field of induced pluripotent stem cell (iPSC) technology offer new possibilities to better understand and potentially reverse disease pathology. Given the neurodevelopmental phenotypes observed in several types of ataxias, iPSC-based models have the potential to provide significant insights into disease progression, as well as opportunities for the development of early intervention therapies. To date, however, very few studies have successfully used iPSC-derived cells to model cerebellar ataxias. In this review, we focus on recent breakthroughs in generating human iPSC-derived Purkinje cells. We also highlight the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.

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Neurons and cardiomyocytes derived from induced pluripotent stem cells as a model for mitochondrial defects in Friedreich's ataxia

Cited by 135 publications

References 50 publications

Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming

Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming

A novel approach of human embryonic stem cells therapy in treatment of Friedrich's Ataxia

Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

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