Multicellular models of Friedreich ataxia

Puccio, Hélène

doi:10.1007/s00415-009-1004-1

Cited by 44 publications

(34 citation statements)

References 43 publications

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“…The high evolutionary conservation of frataxin across the species has enabled the development of disease models in various organisms, from the unicellular eukaryote Saccharomyces cerevisiae to the complex multicellular mouse model. Depending on the frataxin expression levels, various models of FRDA have shown that different, and even opposite, phenotypes can be observed (reviewed in [23], [24]). Therefore, a combination of studies is needed for the better understanding of the pathophysiological functions of frataxin.…”

Section: Introductionmentioning

confidence: 99%

Generation and Characterisation of Friedreich Ataxia YG8R Mouse Fibroblast and Neural Stem Cell Models

Sandi

Jassal

et al. 2014

PLoS ONE

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BackgroundFriedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by GAA repeat expansion in the first intron of the FXN gene, which encodes frataxin, an essential mitochondrial protein. To further characterise the molecular abnormalities associated with FRDA pathogenesis and to hasten drug screening, the development and use of animal and cellular models is considered essential. Studies of lower organisms have already contributed to understanding FRDA disease pathology, but mammalian cells are more related to FRDA patient cells in physiological terms.Methodology/Principal FindingsWe have generated fibroblast cells and neural stem cells (NSCs) from control Y47R mice (9 GAA repeats) and GAA repeat expansion YG8R mice (190+120 GAA repeats). We then differentiated the NSCs in to neurons, oligodendrocytes and astrocytes as confirmed by immunocytochemical analysis of cell specific markers. The three YG8R mouse cell types (fibroblasts, NSCs and differentiated NSCs) exhibit GAA repeat stability, together with reduced expression of frataxin and reduced aconitase activity compared to control Y47R cells. Furthermore, YG8R cells also show increased sensitivity to oxidative stress and downregulation of Pgc-1α and antioxidant gene expression levels, especially Sod2. We also analysed various DNA mismatch repair (MMR) gene expression levels and found that YG8R cells displayed significant reduction in expression of several MMR genes, which may contribute to the GAA repeat stability.Conclusions/SignificanceWe describe the first fibroblast and NSC models from YG8R FRDA mice and we confirm that the NSCs can be differentiated into neurons and glia. These novel FRDA mouse cell models, which exhibit a FRDA-like cellular and molecular phenotype, will be valuable resources to further study FRDA molecular pathogenesis. They will also provide very useful tools for preclinical testing of frataxin-increasing compounds for FRDA drug therapy, for gene therapy, and as a source of cells for cell therapy testing in FRDA mice.

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Section: Introductionmentioning

confidence: 99%

Generation and Characterisation of Friedreich Ataxia YG8R Mouse Fibroblast and Neural Stem Cell Models

Sandi

Jassal

et al. 2014

PLoS ONE

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“…In spite of the availability of multi cellular models for the disease [4, 5], insights into possible therapeutic strategies [6, 7] and broader systematic clinical studies [8], the pathogenesis of Friedreich’s ataxia and its relationship with frataxin remains to be fully understood. Frataxin is a highly conserved protein localized in the mitochondria whose function is associated with iron homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Iron-binding activity in yeast frataxin entails a trade off with stability in the α1/β1 acidic ridge region

Correia

Wang

Craig

et al. 2010

Biochemical Journal

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Synopsis Frataxin is a highly conserved mitochondrial protein whose deficiency in humans results in Friedreich’s ataxia (FRDA), an autosomal recessive disorder characterized by progressive ataxia and cardiomyopathy. Although its cellular function is still not fully clear, the fact that frataxin plays a crucial role in Fe-S assembly on the scaffold protein Isu is well accepted. Here we report the characterisation of eight frataxin variants having alterations on two putative functional regions – the α1/β1 acidic ridge and the conserved β-sheet surface. We report that frataxin iron binding capacity is quite robust: even when five of the most conserved residues from the putative iron binding region are altered, at least 2 iron atoms per monomer can be bound, although with decreased affinity. Furthermore, we conclude that the acidic ridge is designed to favour function over stability. The negative charges have a functional role, but at the same time significantly impair frataxin’s stability. Removing five of those charges results in a thermal stabilization of ~24°C and reduces the inherent conformational plasticity. Alterations on the conserved β-sheet residues have only a modest impact on the protein stability, highlighting the functional importance of residues 122-124.

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“…1). Dabei können einzelne Aspekte der Pathogenese spezieller Krankheitsbilder häufig schon in einfach konstruierten Wirbellosen, wie Würmern und Fliegen, untersucht werden [1,2], während die Analyse komplexer Krankheitsvorgänge und insbesondere die Erprobung neuer therapeutischer Verfahren selbst in Primaten nur mit großen Einschränkungen auf die klinische Situation über-tragbar ist [3 -6]. Natürlicherweise können die vielfältigen Phäno-typen der zumeist sehr heterogenen neurologischen Krankheiten nicht in einem einzelnen Tiermodell reproduziert werden.…”

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“…In gentechnisch manipulierten Tieren werden pathogenetisch bedeutsame Gene entweder permanent oder konditioniert (räumlich und zeitlich begrenzt) ausgeschaltet (Knockout-Tiere) oder überexprimiert (Knockin-Tiere, transgene Tiere) [25,27]. Auf diese Weise sind u. a. EAE-Mäuse generiert worden, die MHC-Moleküle, Rezeptoren für Myelinantigene oder Zytokine und ihre Rezeptoren überexprimieren [25,28], darunter auch solche menschlicher Herkunft in sogenannten "humanisierten" Mäusen [2,28]. Andere Krankheitsmodelle werden durch die Einführung von mutierten Genen erzeugt, die beim Menschen hereditäre Krankheiten auslösen.…”

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Tiermodelle in der Neurologie: Möglichkeiten und Grenzen

Mix¹,

Meyer-Rienecker²,

Zettl³

2009

Fortschr Neurol Psychiatr

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Animal models play an important role for exploration of the aetiology, pathogenesis and therapy of various neurological diseases. Their benefit and limitations are being discussed mainly focussed at experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). To answer specific questions concerning the genetics, pathogenesis, diagnostics and treatment of inflammatory, degenerative, ischemic, traumatic und neoplastic diseases of the nervous system different animal models are needed. So far, these are only partially available. Rarely there are alternative methods such as cell, tissue and organ cultures and computer simulations. New phase-specific biomarkers are needed in order to improve the potency of experimental results to be translated into clinical practice.

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Multicellular models of Friedreich ataxia

Cited by 44 publications

References 43 publications

Generation and Characterisation of Friedreich Ataxia YG8R Mouse Fibroblast and Neural Stem Cell Models

Generation and Characterisation of Friedreich Ataxia YG8R Mouse Fibroblast and Neural Stem Cell Models

Iron-binding activity in yeast frataxin entails a trade off with stability in the α1/β1 acidic ridge region

Tiermodelle in der Neurologie: Möglichkeiten und Grenzen

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