The Structure and Function of Frataxin

Bencze, Krisztina Z.; Kondapalli, Kalyan C.; Cook, Jeremy D.; McMahon, Stephen B.; Millán‐Pacheco, César; Pastor, Nina; Stemmler, Timothy L.

doi:10.1080/10409230600846058

Cited by 144 publications

(117 citation statements)

References 141 publications

(208 reference statements)

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“…The decrease in frataxin protein has broad, far-reaching effects because the protein is an essential iron chaperone required for the biogenesis of iron-sulfur clusters, aconitase activation, and heme biosynthesis [18][19][20][21], and further performs a critical role in iron detoxification and anti-oxidant protection [22][23][24]. Thus a loss of frataxin leads to widespread impairment of energy metabolism, increased oxidative stress, and a generally dysregulated iron metabolism, including accumulation of iron in the heart and nervous system [25].…”

Section: Introductionmentioning

confidence: 99%

Lateral-flow immunoassay for the frataxin protein in Friedreich’s ataxia patients and carriers

Willis¹,

Isaya

Gakh

et al. 2008

Molecular Genetics and Metabolism

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Friedreich's Ataxia (FA) is an inherited neurodegenerative disease caused by reduction in levels of the mitochondrial protein frataxin. Currently there are no simple, reliable methods to accurately measure the concentrations of frataxin protein. We designed a lateral-flow immunoassay that quantifies frataxin protein levels in a variety of sample materials. Using recombinant frataxin we evaluated the accuracy and reproducibility of the assay. The assay measured recombinant human frataxin concentrations between 40 and 4000 pg/test or approximately 0.1 -10 nM of sample. The intra and inter-assay error was < 10% throughout the working range. To evaluate clinical utility of the assay we used genetically defined lymphoblastoid cells derived from FA patients, FA carriers and controls. Mean frataxin concentrations in FA patients and carriers were significantly different from controls and from one another (p = 0.0001, p = 0.003, p = 0.005, respectively) with levels, on average, 29% (patients) and 64% (carriers) of the control group. As predicted, we observed an inverse relationship between GAA repeat number and frataxin protein concentrations within the FA patient cohort. The lateral flow immunoassay provides a simple, accurate and reproducible method to quantify frataxin protein in whole cell and tissue extracts, including primary samples obtained by non-invasive means, such as cheek swabs and whole blood. The assay is a novel tool for FA research that may facilitate improved diagnostic and prognostic evaluation of FA patients and could also be used to evaluate efficacy of therapies designed to cure FA by increasing frataxin protein levels.

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Section: Introductionmentioning

confidence: 99%

Lateral-flow immunoassay for the frataxin protein in Friedreich’s ataxia patients and carriers

Willis¹,

Isaya

Gakh

et al. 2008

Molecular Genetics and Metabolism

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“…Although FXN knockout mice and cell lines are important tools for understanding the role of frataxin in cell physiology and disease etiology and progression (Bencze et al, 2006;Puccio, 2007;Puccio et al, 2001), these resources are not appropriate for discovery of FXN gene activators. For that purpose, several groups have developed transgenic mice harboring FXN alleles with expanded GAA·TTC repeats and reporter cell lines.…”

Section: Development Of Cell Lines and Mouse Models For Frdamentioning

confidence: 99%

“…This review will focus on the identification and characterization of such molecules. Recent excellent reviews have focused on the etiology of FRDA (Lodi et al, 2006), the role of frataxin protein in mitochondrial function and cell metabolism (Bencze et al, 2006;Calabrese et al, 2005), and the development of anti-oxidants, iron chelators and other chemical modifiers of mitochondrial function as FRDA therapeutics (Boddaert et al, 2007;Lodi et al, 2006;Shults and Haas, 2005); hence, these topics will not be covered here.…”

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confidence: 99%

Small molecules affecting transcription in Friedreich ataxia

Gottesfeld

2007

Pharmacology & Therapeutics

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This review concerns the development of small molecule therapeutics for the inherited neurodegenerative disease Friedreich ataxia (FRDA). FRDA is caused by transcriptional repression of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin, and accompanying loss of frataxin protein. Frataxin insufficiency leads to mitochrondrial dysfunction and progressive neurodegeneration, along with scoliosis, diabetes and cardiomyopathy. Individuals with FRDA generally die in early adulthood from the associated heart disease, the most common cause of death in FRDA. While anti-oxidants and iron chelators have shown promise in ameliorating the symptoms of the disease, there is no effective therapy for FRDA that addresses the cause of the disease, the loss of frataxin protein. Gene therapy and protein replacement strategies for FRDA are promising approaches; however, current technology is not sufficiently advanced to envisage treatments for FRDA coming from these approaches in the near future. Since the FXN mutation in FRDA, expanded GAA·TTC triplets in an intron, does not alter the amino acid sequence of frataxin protein, gene reactivation would be of therapeutic benefit. Thus, a number of laboratories have focused on small molecule activators of FXN gene expression as potential therapeutics, and this review summarizes the current status of these efforts as well as the molecular basis for gene silencing in FRDA.

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“…Each [2Fe-2S] cluster-coordinating site is close to conserved residues of Yfh1 known to be involved in iron binding (Fig. 9B) (22,59). Three putative iron coordinating sites of Yfh1 were identified and modeled after aligning the structures of ironbound Yfh1…”

Section: Cross-linked Partners Total Cross-linked Peptidesmentioning

confidence: 99%

Architecture of the Yeast Mitochondrial Iron-Sulfur Cluster Assembly Machinery

Ranatunga

Gakh

Galeano

et al. 2016

Journal of Biological Chemistry

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The biosynthesis of Fe-S clusters is a vital process involving the delivery of elemental iron and sulfur to scaffold proteins via molecular interactions that are still poorly defined. Furthermore, molecular modeling suggests that two subunits of the cysteine desulfurase, Nfs1, may bind symmetrically on top of two adjacent Isu1 trimers in a manner that creates two putative [2Fe-2S] cluster assembly centers. In each center, conserved amino acids known to be involved in sulfur and iron donation by Nfs1 and Yfh1, respectively, are in close proximity to the Fe-S cluster-coordinating residues of Isu1. We suggest that this architecture is suitable to ensure concerted and protected transfer of potentially toxic iron and sulfur atoms to Isu1 during Fe-S cluster assembly.

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The Structure and Function of Frataxin

Cited by 144 publications

References 141 publications

Lateral-flow immunoassay for the frataxin protein in Friedreich’s ataxia patients and carriers

Lateral-flow immunoassay for the frataxin protein in Friedreich’s ataxia patients and carriers

Small molecules affecting transcription in Friedreich ataxia

Architecture of the Yeast Mitochondrial Iron-Sulfur Cluster Assembly Machinery

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