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)

Friedreich's ataxia is the most frequent inherited ataxia in Caucasians. It is caused by deficiency of frataxin, a highly conserved nuclear-encoded protein localized in mitochondria. The DNA abnormality found in 98% of Friedreich's ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the frataxin gene. Most patients are homozygous for this repeat expansion. The expanded GAA repeat causes frataxin deficiency because it interferes with the transcription of the gene by adopting a non-B (probably triple helical) structure. Longer repeats cause a more profound frataxin deficiency and are associated with earlier onset and increased severity of the disease. Molecular testing has shown that the phenotypic spectrum of Friedreich's ataxia is wider than previously thought. Up to 10% of patients with recessive or sporadic degenerative ataxia who do not fulfill the Friedreich's ataxia diagnostic criteria are homozygous for expanded alleles at the Friedreich's ataxia locus. Late age of onset, retained tendon reflexes, and lack of pyramidal signs are among the atypical features observed in some patients with a positive molecular test. Yeast cells deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich's ataxia is caused by mitochondrial dysfunction and free radical toxicity, with consequent mitochondrial damage, axonal degeneration, and cell death.
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PMID:Friedreich's ataxia: clinical aspects and pathogenesis. 1219 87

Friedreich's ataxia is caused by a deficit in frataxin, a small mitochondrial protein of unknown function that has been conserved during evolution. Previous studies have pointed out a role for frataxin in mitochondrial iron-sulfur (Fe-S) metabolism. Here, we have analyzed the incorporation of Fe-S clusters into yeast ferredoxin imported into isolated energized mitochondria from cells grown in the presence of glycerol, an obligatory respiratory carbon source. Similar amounts of apo-ferredoxin precursor were imported into mitochondria and processed in wild-type and yfh1-deleted (delta YF111) strains. However, the incorporation of Fe-S clusters into apo-ferredoxin was significantly reduced in delta YFH1 mitochondria. The newly assembled ferredoxin was stable, excluding the possibility that the decreased incorporation was a result of increased oxidative damage. When delta YFH1 cells were grown in raffinose medium, the formation of holo-ferredoxin was low, as a consequence of the decrease in ferredoxin precursor import into mitochondria. However, the decrease in the conversion rate of apo- into holo-ferredoxin was in the same range as for glycerol-grown cells, indicating that the extent of the defect in Fe-S protein assembly is similar under different physiological conditions. These data show that frataxin is not essential for Fe-S protein assembly, but improves the efficiency of the process. The large variations observed in the activity of Fe-S cluster proteins under different physiological conditions result from secondary defects in the physiology of delta YFH1 cells.
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PMID:A non-essential function for yeast frataxin in iron-sulfur cluster assembly. 1235 89

Iron is a vitally important element in mammalian metabolism because of its unsurpassed versatility as a biologic catalyst. However, when not appropriately shielded or when present in excess, iron plays a key role in the formation of extremely toxic oxygen radicals, which ultimately cause peroxidative damage to vital cell structures. Organisms are equipped with specific proteins designed for iron acquisition, export, transport, and storage as well as with sophisticated mechanisms that maintain the intracellular labile iron pool at an appropriate level. These systems normally tightly control iron homeostasis but their failure can lead to iron deficiency or iron overload and their clinical consequences. This review describes several rare iron loading conditions caused by genetic defects in some of the proteins involved in iron metabolism. A dramatic decrease in the synthesis of the plasma iron transport protein, transferrin, leads to a massive accumulation of iron in nonhematopoietic tissues but virtually no iron is available for erythropoiesis. Humans and mice with hypotransferrinemia have a remarkably similar phenotype. Homozygous defects in a recently identified gene encoding transferrin receptor 2 lead to iron overload (hemochromatosis type 3) with symptoms similar to those seen in patients with HFE-associated hereditary hemochromatosis (hemochromatosis type 1). Transferrin receptor 2 is primarily expressed in the liver but it is unclear how mutant forms cause iron overload. Mutations in the gene encoding the iron exporter, ferroportin 1, cause iron overload characterized by iron accumulation in macrophages yet normal plasma iron levels. Plasma iron, together with dominant inheritance, discriminates iron overload due to ferroportin mutations (hemochromatosis type 4) from hemochromatosis type 1. Heme oxygenase 1 is essential for the catabolism of heme and in the recycling of hemoglobin iron in macrophages. Homozygous heme oxygenase 1 deletion in mice leads to a paradoxical accumulation of nonheme iron in macrophages, hepatocytes, and many other cells and is associated with low plasma iron levels, anemia, endothelial cell damage, and decreased resistance to oxidative stress. A similar phenotype occurred in a child with severe heme oxygenase 1 deficiency. Recently, a mutation in the L-subunit of ferritin has been described that causes the formation of aberrant L-ferritin with an altered C-terminus. Individuals with this mutation in one allele of L-ferritin have abnormal aggregates of ferritin and iron in the brain, primarily in the globus pallidus. Patients with this dominantly inherited late-onset disease present with symptoms of extrapyramidal dysfunction. Mice with a targeted disruption of a gene for iron regulatory protein 2 (IRP2), a translational repressor of ferritin, misregulate iron metabolism in the intestinal mucosa and the central nervous system. Significant amounts of ferritin and iron accumulate in white matter tracts and nuclei, and adult IRP2-deficient mice develop a movement disorder consisting of ataxia, bradykinesia, and tremor. Mutations in the frataxin gene are responsible for Friedreich ataxia, the most common of the inherited ataxias. Frataxin appears to regulate mitochondrial iron (or iron-sulfur cluster) export and the neurologic and cardiac manifestations of Friedreich ataxia are due to iron-mediated mitochondrial toxicity. Finally, patients with Hallervorden-Spatz syndrome, an autosomal recessive, progressive neurodegenerative disorder, have mutations in a novel pantothenate kinase gene (PANK2). The cardinal feature of this extrapyramidal disease is pathologic iron accumulation in the globus pallidus. The defect in PANK2 is predicted to cause the accumulation of cysteine, which binds iron and causes oxidative stress in the iron-rich globus pallidus.
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PMID:Rare causes of hereditary iron overload. 1238

Iron, an essential element for central nervous system (CNS) function, has frequently been found to accumulate in brain regions that undergo degeneration in neurological diseases such as Alzheimer disease, Parkinson disease, Friedreich ataxia and other disorders. However, the precise role of iron in the cause of many neurodegenerative diseases is unclear. To assist in understanding the potential importance of iron in CNS disease, this review summarizes the present knowledge in the areas of CNS iron metabolism, homeostasis and disregulation of iron balance caused by mutations in genes encoding proteins involved in iron transport, storage and metabolism. This review encompasses neurodegenerative disorders associated with both iron overload and deficiency to highlight areas where iron misregulation is likely to be important in the pathophysiology of several human brain diseases.
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PMID:Brain iron metabolism and neurodegenerative disorders. 1240 58

Friedreich ataxia is an autosomal recessive disease causing degeneration in the central and peripheral nervous system, cardiomyopathy, skeletal abnormalities and increased risk of diabetes. It is caused by deficiency of frataxin, a highly conserved nuclear-encoded mitochondrial protein. The genetic mutation found in 98% of Friedreich ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the gene. The expanded GAA repeat, by adopting an abnormal triple helical structure, impairs frataxin transcription. Longer repeats cause a more profound frataxin deficiency and are associated with earlier onset and increased severity of the disease. Yeast cells deficient in the frataxin homologue (Deltayfh1) become unable to carry out oxidative phosphorylation, lose mitochondrial DNA, accumulate iron in mitochondria, show unregulated high expression of high affinity iron uptake, and have an increased sensitivity to oxidative stress. Loss of respiratory competence in Deltayfh1 is iron-dependent. Additional properties of these cells include a deficiency of iron-sulfur cluster containing proteins (ISPs) and impaired iron efflux out of mitochondria. Evidence of oxidative stress, mitochondrial dysfunction, deficiency of multiple ISPs and iron deposits are also found in the human disease and in mouse models. The primary function of frataxin is still unknown, however much recent evidence suggests that it enhances iron-sulfur cluster synthesis and protects iron from free radical-generating reactions. The search for frataxin function stimulated more investigations on the role of mitochondria in cellular iron homeostasis. Their results suggest that these organelles may play a central role in controlling iron homeostasis, which is not surprising considering that they are the major cellular site where this metal is utilized. I propose a model, valid in yeast as well as in higher eukaryotes, in which iron transport into mitochondria is directly coupled to its uptake at the cell membrane and iron transport out of mitochondria depends on adequate iron-sulfur cluster synthesis. Regulatory mechanisms in the cytosol would then sense a post-mitochondrial iron pool. Much circumstantial evidence from genetically manipulated yeast and from human diseases supports this model.
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PMID:Iron metabolism and mitochondrial abnormalities in Friedreich ataxia. 1254 48

Friedreich's ataxia (FA) is a severe inherited spinocerebellar ataxia that primarily affects the nervous system and heart leading to early confinement in a wheelchair and death. The gene defective in FA, FRDA, encodes a mitochondrial protein known as frataxin. A triplet repeat expansion within intron 1 of the FRDA gene results in a marked decrease in frataxin expression. Over the last 5 years it has become clear that this results in mitochondrial iron accumulation that generates oxidative stress and results in damage to critical biological molecules. Drugs that reduce oxidative stress have a limited effect on the progression and pathology of the disease, probably because these agents cannot remove the iron accumulation. In this review, the potential of iron chelators, namely the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) analogues, as agents to remove mitochondrial iron deposits is discussed. These ligands have been specifically designed to enter and target mitochondrial iron pools, which is a property lacking in desferrioxamine, the only chelator in widespread clinical use. This latter drug may not have any beneficial effect in FA patients, probably because of its hydrophilicity that prevents mitochondrial access. Indeed, standard chelation regimens will probably not work in FA, as these patients do not exhibit gross iron-loading. Considering that there is no effective treatment for FA, it is essential that the therapeutic potential of iron chelators that target mitochondrial iron pools is assessed experimentally.
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PMID:Friedreich's ataxia: iron chelators that target the mitochondrion as a therapeutic strategy? 1255 17

Friedreich's ataxia is the most common recessive ataxia associated with life-threatening cardiomyopathy. It results from a loss of function of frataxin that ultimately leads to oxidative insult, particularly to neurons and cardiomyocytes. The disease is progressive, the oxidative insult being presumably subsequent to an abnormal iron/sulfur cluster synthesis that causes mitochondrial respiratory chain disease and impaired signalling of one antioxidant pathway. After a detailed in vitro study, idebenone, a short chain homologue of coenzyme Q(10) with potent antioxidant properties, was given to patients. The antioxidant had a dramatic and rapid effect on the cardiomyopathy in most patients. Although a subset of patients also report various improvements, implying that idebenone could have a broader spectrum of action including some neurological improvements, the antioxidant did not have noticeable effects on the ataxia. Several hypotheses on the mechanisms that could account for the contrasting effects of the antioxidant on clinical symptoms of Friedreich's ataxia are discussed in this review. The considerable difficulties still being encountered in ascertaining the effect of antioxidants on the course of the neurological condition are also considered.
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PMID:The use of antioxidants in Friedreich's ataxia treatment. 1266 13

There is considerable evidence suggesting that mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Parkinson's disease (PD). This possibility has been strengthened by recent studies in animal models, which have shown that a selective inhibitor of complex I of the electron transport gene can produce an animal model that closely mimics both the biochemical and histopathological findings of PD. Several agents are available that can modulate cellular energy metabolism and that may exert antioxidative effects. There is substantial evidence that mitochondria are a major source of free radicals within the cell. These appear to be produced at both the iron-sulfur clusters of complex I as well as the ubiquinone site. Agents that have shown to be beneficial in animal models of PD include creatine, coenzyme Q(10), Ginkgo biloba, nicotinamide, and acetyl-L-carnitine. Creatine has been shown to be effective in several animal models of neurodegenerative diseases and currently is being evaluated in early stage trials in PD. Similarly, coenzyme Q(10) is also effective in animal models and has shown promising effects both in clinical trials of PD as well as in clinical trials in Huntington's disease and Friedreich's ataxia. Many other agents show good human tolerability. These agents therefore are promising candidates for further study as neuroprotective agents in PD.
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PMID:Bioenergetic approaches for neuroprotection in Parkinson's disease. 1266 97

Heme and iron metabolism are of considerable interest and importance in normal brain function as well as in neurodegeneration and neuropathologically following traumatic injury and hemorrhagic stroke. After a cerebral hemorrhage, large numbers of hemoglobin-containing red blood cells are released into the brain's parenchyma and/or subarachnoid space. After hemolysis and the subsequent release of heme from hemoglobin, several pathways are employed to transport and metabolize this heme and its iron moiety to protect the brain from potential oxidative stress. Required for these processes are various extracellular and intracellular transporters and storage proteins, the heme oxygenase isozymes and metabolic proteins with differing localizations in the various brain-cell types. In the past several years, additional new genes and proteins have been discovered that are involved in the transport and metabolism of heme and iron in brain and other tissues. These discoveries may provide new insights into neurodegenerative diseases like Alzheimer's, Parkinson's, and Friedrich's ataxia that are associated with accumulation of iron in specific brain regions or in specific organelles. The present review will examine the uptake and metabolism of heme and iron in the brain and will relate these processes to blood removal and to the potential mechanisms underlying brain injury following cerebral hemorrhage.
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PMID:Heme and iron metabolism: role in cerebral hemorrhage. 1279 11

Inherited deficiency of the mitochondrial protein frataxin causes neural and cardiac cell degeneration, and Friedreich's ataxia. Five hypotheses for frataxin's mitochondrial function have been generated, largely from work in non-human cells: iron transporter, iron-sulfur cluster assembler, iron-storage protein, antioxidant and stimulator of oxidative phosphorylation. We analyzed gene expression in three human cell types using microarrays, and identified just 48 transcripts whose expression was significantly frataxin-dependent in at least two cell types. Significant decreases in seven transcripts occurred in the sulfur amino acid (SAA) biosynthetic pathway and the iron-sulfur cluster (ISC) biosynthetic pathway to which it is connected. By contrast, we did not observe a single frataxin-dependent transcript that fits with the other four current hypotheses. Quantitative reverse-transcriptase PCR analysis of ISC-S and rhodanese transcripts confirmed that the expression of these genes involved in ISC metabolism was lower in mutants. Amino acid analysis confirmed the defect in SAA metabolism: homocystine, cysteine, cystathionine and serine were significantly decreased in frataxin-deficient cell extracts and mitochondria. An ISC defect was further confirmed by observing decreases in succinate dehydrogenase and aconitase activities, whose activities require ISCs. The ISC-U scaffold protein was specifically decreased in frataxin-deficient cells, suggesting a role for frataxin in its expression or maintenance, and sodium sulfide partially rescued the oxidant-sensitivity of the FRDA cells. Also, multiple transcripts involved in the Fas/TNF/INF apoptosis pathway were up-regulated in frataxin-deficient cells, consistent with a multi-step mechanism of Friedreich's ataxia pathophysiology, and suggesting alternative possibilities for therapeutic intervention.
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PMID:Decreased expression of genes involved in sulfur amino acid metabolism in frataxin-deficient cells. 1283 93


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