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)

There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration. The precise sequence of events in FRDA pathogenesis is uncertain. The impaired intramitochondrial metabolism with increased free iron levels and a defective mitochondrial respiratory chain, associated with increased free radical generation and oxidative damage, may be considered possible mechanisms that compromise cell viability. Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols, and in addition, that decreased expression of frataxin protein is associated with FRDA. Many approaches have been undertaken to understand FRDA, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to FRDA pathogenesis. Brains of FRDA patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress. In the central nervous system, heat shock protein (HSP) synthesis is induced not only after hyperthermia, but also following alterations in the intracellular redox environment. The major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease (HD) and FRDA are all associated with the presence of abnormal proteins. Among the various HSPs, HSP32, also known as heme oxygenase I (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. This may open up new perspectives in medicine, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms, such as the heat shock response, through nutritional antioxidants, pharmacological compounds or gene transduction, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.
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PMID:Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia. 1589 10

Friedreich's ataxia, an autosomal cardio- and neurodegenerative disorder that affects 1 in 50,000 humans, is caused by decreased levels of the protein frataxin. Although frataxin is nuclear-encoded, it is targeted to the mitochondrial matrix and necessary for proper regulation of cellular iron homeostasis. Frataxin is required for the cellular production of both heme and iron-sulfur (Fe-S) clusters. Monomeric frataxin binds with high affinity to ferrochelatase, the enzyme involved in iron insertion into porphyrin during heme production. Monomeric frataxin also binds to Isu, the scaffold protein required for assembly of Fe-S cluster intermediates. These processes (heme and Fe-S cluster assembly) share requirements for iron, suggesting that monomeric frataxin might function as the common iron donor. To provide a molecular basis to better understand frataxin's function, we have characterized the binding properties and metal-site structure of ferrous iron bound to monomeric yeast frataxin. Yeast frataxin is stable as an iron-loaded monomer, and the protein can bind two ferrous iron atoms with micromolar binding affinity. Frataxin amino acids affected by the presence of iron are localized within conserved acidic patches located on the surfaces of both helix-1 and strand-1. Under anaerobic conditions, bound metal is stable in the high-spin ferrous state. The metal-ligand coordination geometry of both metal-binding sites is consistent with a six-coordinate iron-(oxygen/nitrogen) based ligand geometry, surely constructed in part from carboxylate and possibly imidazole side chains coming from residues within these conserved acidic patches on the protein. On the basis of our results, we have developed a model for how we believe yeast frataxin interacts with iron.
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PMID:Monomeric yeast frataxin is an iron-binding protein. 1678 28

Nitric oxide (NO), plays multiple roles in the nervous system. In addition to regulating proliferation, survival and differentiation of neurons, NO is involved in synaptic activity, neural plasticity, and memory function. Nitric oxide promotes survival and differentiation of neural cells and exerts long-lasting effects through regulation of transcription factors and modulation of gene expression. Signaling by reactive nitrogen species is carried out mainly by targeted modifications of critical cysteine residues in proteins, including S-nitrosylation and S-oxidation, as well as by lipid nitration. NO and other reactive nitrogen species are also involved in neuroinflammation and neurodegeneration, such as in Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, multiple sclerosis, Friedreich ataxia, and Huntington disease. Susceptibility to NO and peroxynitrite exposure may depend on factors such as the intracellular reduced glutathione and cellular stress resistance signaling pathways. Thus, neurons, in contrast to astrocytes, appear particularly vulnerable to the effects of nitrosative stress. This article reviews the current understanding of the cytotoxic versus cytoprotective effects of NO in the central nervous system, highlighting the Janus-faced properties of this small molecule. The significance of NO in redox signaling and modulation of the adaptive cellular stress responses and its exciting future perspectives also are discussed.
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PMID:Nitric oxide in cell survival: a janus molecule. 1955 11

Iron is a redox active metal involved in the oxidation-reduction reactions and regulation of cell growth and differentiation. Iron is an integral part of many proteins and enzymes that maintains various physiological functions. Most of the human body's iron is contained in red blood cells. Despite iron being an abundant trace metal in food, millions of people worldwide suffer from anemia. Iron deficiency results in impaired production of iron-containing proteins and inhibition of cell growth. In contrast, abnormal iron uptake has been related to the most common hereditary disease hemochromatosis, leading to tissue damage derived from free radical toxicity. In addition, disruption of iron regulation plays a key role in the etiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedreich's ataxia and other neurological disorders, cancer (lung cancer, breast cancer, colon cancer), Fanconi anemia, stroke and ageing. Thus the control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease. The most frequent is the toxic role of iron linked with the catalytic decomposition of hydrogen peroxide (Fenton reaction) leading to the formation of reactive oxygen species (ROS) causing damage to biomolecules, including lipids, proteins and DNA. The binding of iron-designed chelators via nitrogen, oxygen or sulphur donor atoms blocks iron s ability to catalyze the formation of free radicals. Thus the design of various metal chelators to prevent free radical reactions is an important approach in the treatment of many iron-related diseases. The development of effective dual functioning antioxidants, possessing both metal-chelating and free radical-scavenging properties is awaited. The aim of this review is to discuss the role of iron and importance of iron-chelation in human disease and ageing.
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PMID:Importance of iron chelation in free radical-induced oxidative stress and human disease. 2190 63

This review will summarise the current state of our knowledge concerning the involvement of iron in various neurological diseases and the potential of therapy with iron chelators to retard the progression of the disease. We first discuss briefly the role of metal ions in brain function before outlining the way by which transition metal ions, such as iron and copper, can initiate neurodegeneration through the generation of reactive oxygen and nitrogen species. This results in protein misfolding, amyloid production and formation of insoluble protein aggregates which are contained within inclusion bodies. This will activate microglia leading to neuroinflammation. Neuroinflammation plays an important role in the progression of the neurodegenerative diseases, with activated microglia releasing pro-inflammatory cytokines leading to cellular cell loss. The evidence for metal involvement in Parkinson's and Alzheimer's disease as well as Friedreich's ataxia and multiple sclerosis will be presented. Preliminary results from trials of iron chelation therapy in these neurodegenerative diseases will be reviewed.
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PMID:Neurodegenerative diseases and therapeutic strategies using iron chelators. 2571

Reactive species play an important role in physiological functions. Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species along with the failure of balance by the body's antioxidant enzyme systems results in destruction of cellular structures, lipids, proteins, and genetic materials such as DNA and RNA. Moreover, the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Multiple sclerosis, and Parkinson's diseases. In addition, oxidative stress causing protein misfold may turn to other NDDs include Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review.
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PMID:Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. 2780 6

: Oxidative stress is an imbalance between production and accumulation of oxygen reactive species and/or reactive nitrogen species in cells and tissues, and the capacity of detoxifying these products, using enzymatic and non-enzymatic components, such as glutathione. Oxidative stress plays roles in several pathological processes in the nervous system, such as neurotoxicity, neuroinflammation, ischemic stroke, and neurodegeneration. The concepts of oxidative stress and rare diseases were formulated in the eighties, and since then, the link between them has not stopped growing. The present review aims to expand knowledge in the pathological processes associated with oxidative stress underlying some groups of rare diseases: Friedreich's ataxia, diseases with neurodegeneration with brain iron accumulation, Charcot-Marie-Tooth as an example of rare neuromuscular disorders, inherited retinal dystrophies, progressive myoclonus epilepsies, and pediatric drug-resistant epilepsies. Despite the discrimination between cause and effect may not be easy on many occasions, all these conditions are Mendelian rare diseases that share oxidative stress as a common factor, and this may represent a potential target for therapies.
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PMID:Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration. 3232 94