Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016719 (Friedreich's ataxia)
 2,098 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Frataxin is an essential mitochondrial protein whose reduced expression causes Friedreich's ataxia (FRDA), a lethal neurodegenerative disease. It is believed that frataxin is an iron chaperone that participates in iron metabolism. We have tested this hypothesis using the bacterial frataxin ortholog, CyaY, and different biochemical and biophysical techniques. We observe that CyaY participates in iron-sulfur (Fe-S) cluster assembly as an iron-dependent inhibitor of cluster formation, through binding to the desulfurase IscS. The interaction with IscS involves the iron binding surface of CyaY, which is conserved throughout the frataxin family. We propose that frataxins are iron sensors that act as regulators of Fe-S cluster formation to fine-tune the quantity of Fe-S cluster formed to the concentration of the available acceptors. Our observations provide new perspectives for understanding FRDA and a mechanistic model that rationalizes the available knowledge on frataxin.
Nat Struct Mol Biol 2009 Apr
PMID:Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS. 1930 5

Peptide nucleic acids (PNAs) are DNA mimics in which peptide-like linkages are substituted for the phosphodiester backbone. Homopyrimidine PNAs can invade double-stranded DNA containing the homologous sequence by displacing the homopyrimidine strand from the DNA duplex and forming a PNA/DNA/PNA triplex with the complementary homopurine strand. Among biologically interesting targets for triplex-forming PNA are (GAA/CTT)(n) repeats. Expansion of these repeats results in partial inhibition of transcription in the frataxin gene, causing Friedreich's ataxia. We have studied PNA binding and its effect on T7 RNA polymerase transcription in vitro for short repeats (n = 3) and for long repeats (n = 39), placed in both possible orientations relative to the T7 promoter such that either the GAA-strand, or the CTT-strand serves as the template for transcription. In all cases PNA bound specifically and efficiently to its target sequence. For the short insert, PNA binding to the template strand caused partial transcription blockage with well-defined sites of RNA product truncation in the region of the PNA-binding sequence, whereas binding to the nontemplate strand did not block transcription. However, PNA binding to long repeats, whether in the template or the nontemplate strand, resulted in a dramatic reduction of the amount of full-length transcription product, although in the case of the nontemplate strand there were no predominant truncation sites. Biological implications of these results are discussed.
Mol Carcinog 2009 Apr
PMID:Peptide nucleic acid (PNA) binding and its effect on in vitro transcription in friedreich's ataxia triplet repeats. 1930 9

Friedreich's ataxia (FRDA), the most common inherited ataxia, is characterized by focal neurodegeneration, diabetes mellitus and life-threatening cardiomyopathy. Frataxin, which is significantly reduced in patients with this recessive disorder, is a mitochondrial iron-binding protein, but how its deficiency leads to neurodegeneration and metabolic derangements is not known. We performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPARgamma) pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of the PPARgamma coactivator Pgc1a and transcription factor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Finally, we show that genetic modulation of the PPARgamma pathway affects frataxin levels in vitro, supporting PPARgamma as a novel therapeutic target in FRDA.
Hum Mol Genet 2009 Jul 01
PMID:Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARgamma pathway as a therapeutic target in Friedreich's ataxia. 1979 9

Large-scale expansions of DNA repeats are implicated in numerous hereditary disorders in humans. We describe a yeast experimental system to analyze large-scale expansions of triplet GAA repeats responsible for the human disease Friedreich's ataxia. When GAA repeats were placed into an intron of the chimeric URA3 gene, their expansions caused gene inactivation, which was detected on the selective media. We found that the rates of expansions of GAA repeats increased exponentially with their lengths. These rates were only mildly dependent on the repeat's orientation within the replicon, whereas the repeat-mediated replication fork stalling was exquisitely orientation dependent. Expansion rates were significantly elevated upon inactivation of the replication fork stabilizers, Tof1 and Csm3, but decreased in the knockouts of postreplication DNA repair proteins, Rad6 and Rad5, and the DNA helicase Sgs1. We propose a model for large-scale repeat expansions based on template switching during replication fork progression through repetitive DNA.
Mol Cell 2009 Jul 10
PMID:Large-scale expansions of Friedreich's ataxia GAA repeats in yeast. 1959 18

Friedreich's ataxia is a neurodegenerative disease caused by the low expression of frataxin, a mitochondrial iron-binding protein which plays an important, but non-essential, role in the formation of iron-sulfur (Fe/S) clusters. It has been shown that Yfh1, the yeast frataxin homologue, interacts functionally and physically with Isu1, the scaffold protein on which the Fe/S clusters are assembled. The large beta-sheet platform of frataxin is a good ligand candidate for this interaction. We have generated 12 yeast mutants in conserved residues of the beta-sheet protruding at the surface or buried in the protein core. The Q129A, I130A, W131A(F) and R141A mutations, which reside in surface exposed residues of the fourth and fifth beta-strands, result in severe cell growth inhibition on high-iron media and low aconitase activity, indicating that Fe/S cluster biosynthesis is impaired. The null phenotype of the I130A mutant results from the high instability of the protein, pointing that this buried residue is essential for folding. In contrast, Gln-129, Trp-131 and Arg-141 residues which are spatially closely clustered define a patch important for protein function. Co-immunoprecipitation experiments using cell extracts show that W131A, unlike W131F, is the sole mutation that strongly decreases the interaction with Isu1. Therefore, Trp-131, which is the only strictly conserved frataxin residue in all sequenced species, appears as a major contributor to the interaction with Isu1 through its surface-exposed aromatic side chain.
Hum Mol Genet 2010 Jan 15
PMID:Frataxin interacts with Isu1 through a conserved tryptophan in its beta-sheet. 1988 69

Friedreich's ataxia is a cardio- and neurodegenerative disease due to decreased expression of the mitochondrial protein, frataxin. This defect results in mitochondrial iron-overload, and in this review, we discuss the mechanisms that lead to this iron accumulation. Using a conditional knockout mouse model where frataxin is deleted in the heart, it has been shown that this mutation leads to transferrin receptor-1 upregulation, resulting in increased iron uptake from transferrin. There is also marked downregulation of ferritin that is required for iron storage and decreased expression of the iron exporter, ferroportin 1, leading to decreased cellular iron efflux. The increased mitochondrial iron uptake is facilitated by upregulation of the mitochondrial iron transporter, mitoferrin 2. This stimulation of iron uptake probably attempts to rescue the deficit in mitochondrial iron metabolism that is due to downregulation of mitochondrial iron utilization, namely, heme and iron-sulfur cluster (ISC) synthesis and also iron storage (mitochondrial ferritin). The resultant decrease in heme and ISC synthesis means heme and ISCs are not exiting the mitochondrion for cytosolic use. Hence, increased mitochondrial iron uptake coupled with decreased utilization and release leads to mitochondrial iron-loading. More generally, disturbance of mitochondrial iron utilization in other diseases probably also results in similar compensatory alterations.
J Mol Med (Berl) 2010 Apr
PMID:The ins and outs of mitochondrial iron-loading: the metabolic defect in Friedreich's ataxia. 1999 98

The inability to produce normal levels of the mitochondrial protein frataxin causes the hereditary degenerative disorder Friedreich's Ataxia (FRDA), a syndrome characterized by progressive gait instability, cardiomyopathy and high incidence of diabetes. Frataxin is an iron-binding protein involved in the biogenesis of iron-sulfur clusters (ISC), prosthetic groups allowing essential cellular functions such as oxidative phosphorylation, enzyme catalysis and gene regulation. Although several evidence suggest that frataxin acts as an iron-chaperone within the mitochondrial compartment, we have recently demonstrated the existence of a functional extramitochondrial pool of mature frataxin in various human cell types. Here, we show that a similar proteolytic process generates both mature mitochondrial and extramitochondrial frataxin. To address the physiological function of human extramitochondrial frataxin, we searched for ISC-dependent interaction partners. We demonstrate that the extramitochondrial form of frataxin directly interacts with cytosolic aconitase/iron regulatory protein-1 (IRP1), a bifunctional protein alternating between an enzymatic and a RNA-binding function through the 'iron-sulfur switch' mechanism. Importantly, we found that the cytosolic aconitase defect and consequent IRP1 activation occurring in FRDA cells are reversed by the action of extramitochondrial frataxin. These results provide new insight into the control of cytosolic aconitase/IRP1 switch and expand current knowledge about the molecular pathogenesis of FRDA.
Hum Mol Genet 2010 Apr 01
PMID:Molecular control of the cytosolic aconitase/IRP1 switch by extramitochondrial frataxin. 2005 67

While many treatments for mitochondrial electron transport (respiratory) chain disorders have been suggested, relatively few have undergone controlled clinical trials. This review focuses on the recent history of clinical trials of dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, and exercise in both primary (congenital) disorders and secondary (degenerative) disorders. Despite prior clinical impressions that DCA had a positive effect on mitochondrial disorders, two trials of diverse subjects failed to demonstrate a clinically significant benefit, and a trial of DCA in MELAS found a major negative effect of neuropathy. Arginine also has been used to treat MELAS with promising effects, although a controlled trial is still needed for this potentially toxic agent. The anti-oxidant coenzyme Q(10) is very widely used for primary mitochondrial disorders but has not yet undergone a controlled clinical trial; such a trial is now underway, as well as trials of the co-Q analogue idebenone for MELAS and LHON. Greater experience has accumulated with multi-center trials of coenzyme Q(10) treatment to prevent the progression of Parkinson disease. Although initial smaller trials indicated a benefit, this has not yet been confirmed in subsequent trials with higher doses; a larger Phase III trial is now underway. Similarly, a series of trials of idebenone for Friedreich ataxia have shown some benefit in slowing the progression of cardiomyopathy, and controlled clinical trials are now underway to determine if there is significant neurological protection. Uncontrolled trials of exercise showed an increase of exercise tolerance in patients with disorders of mitochondrial DNA, but did not selectively increase the percentage of normal mtDNA; a larger partially controlled trial is now underway to evaluate this possible benefit. In summary, none of the controlled trials so far has conclusively shown a benefit of treatment with the agents tested, but some promising therapies are currently being evaluated in a controlled manner. These experiences underscore the importance of controlled clinical trials for evaluation of benefits and risks of recommended therapies. Application of such clinical trials to future more effective therapies for mitochondrial disorders will require multi-center collaboration, organization, leadership, and financial and advocacy support.
Mol Genet Metab 2010 Mar
PMID:Treatment of mitochondrial electron transport chain disorders: a review of clinical trials over the past decade. 2006 Mar 49

Friedreich ataxia is a degenerative disease caused by deficiency of the protein frataxin (FXN). An intronic expansion of GAA triplets in the FXN-encoding gene, FXN, causes gene silencing and thus reduced FXN protein levels. Although it is widely assumed that GAA repeats block transcription via the assembly of an inaccessible chromatin structure marked by methylated H3K9, direct proof for this is lacking. In this study, we analysed different histone modification patterns along the human FXN gene in FRDA patient-derived lymphoblastoid cell lines. We show that FXN mRNA synthesis, but not turnover rates are affected by an expanded GAA repeat tract. Importantly, rather than preventing transcription initiation, long GAA repeat tracts affect transcription at the elongation step and this can occur independently of H3K9 methylation. Our data demonstrate that finding novel strategies to overcome the transcription elongation problem may develop into promising new treatments for FRDA.
EMBO Mol Med 2010 Apr
PMID:Long intronic GAA repeats causing Friedreich ataxia impede transcription elongation. 2037 85

Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin. The physiopathological consequences of frataxin deficiency are a severe disruption of iron-sulfur cluster biosynthesis, mitochondrial iron overload coupled to cellular iron dysregulation and an increased sensitivity to oxidative stress. Frataxin is a highly conserved protein, which has been suggested to participate in a variety of different roles associated with cellular iron homeostasis. The present review discusses recent advances that have made crucial contributions in understanding the molecular mechanisms underlying FRDA and in advancements toward potential novel therapeutic approaches. Owing to space constraints, this review will focus on the most commonly accepted and solid molecular and biochemical studies concerning the function of frataxin and the physiopathology of the disease. We invite the reader to read the following reviews to have a more exhaustive overview of the field [Pandolfo, M. and Pastore, A. (2009) The pathogenesis of Friedreich ataxia and the structure and function of frataxin. J. Neurol., 256 (Suppl. 1), 9-17; Gottesfeld, J.M. (2007) Small molecules affecting transcription in Friedreich ataxia. Pharmacol. Ther., 116, 236-248; Pandolfo, M. (2008) Drug insight: antioxidant therapy in inherited ataxias. Nat. Clin. Pract. Neurol., 4, 86-96; Puccio, H. (2009) Multicellular models of Friedreich ataxia. J. Neurol., 256 (Suppl. 1), 18-24].
Hum Mol Genet 2010 Apr 15
PMID:Understanding the molecular mechanisms of Friedreich's ataxia to develop therapeutic approaches. 2041 54


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