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 and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species and mitochondrial dysfunction. Here, we review the evidence for a disturbance of glutathione homeostasis that may either lead to or result from oxidative stress in neurodegenerative disorders. Glutathione is an important intracellular antioxidant that protects against a variety of different antioxidant species. An important role for glutathione was proposed for the pathogenesis of Parkinson's disease, because a decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable. Because glutathione does not cross the blood-brain barrier other treatment options to increase brain concentrations of glutathione including glutathione analogs, mimetics or precursors are discussed.
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PMID:Glutathione, oxidative stress and neurodegeneration. 1093 Nov 72

Friedreich's ataxia is a neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin. The main phenotypic features of frataxin-deficient human and yeast cells include iron accumulation in mitochondria, iron-sulphur cluster defects and high sensitivity to oxidative stress. Glutathione is a major protective agent against oxidative damage and glutathione-related systems participate in maintaining the cellular thiol/disulfide status and the reduced environment of the cell. Here, we present the first detailed biochemical study of the glutathione-dependent redox status of wild-type and frataxin-deficient cells in a yeast model of the disease. There were five times less total glutathione (GSH+GSSG) in frataxin-deficient cells, imbalanced GSH/GSSG pools and higher glutathione peroxidase activity. The pentose phosphate pathway was stimulated in frataxin-deficient cells, glucose-6-phosphate dehydrogenase activity was three times higher than in wild-type cells and this was coupled to a defect in the NADPH/NADP(+) pool. Moreover, analysis of gene expression confirms the adaptative response of mutant cells to stress conditions and we bring evidence for a strong relation between the glutathione-dependent redox status of the cells and iron homeostasis. Dynamic studies show that intracellular glutathione levels reflect an adaptation of cells to iron stress conditions, and allow to distinguish constitutive stress observed in frataxin-deficient cells from the acute response of wild-type cells. In conclusion, our findings provide evidence for an impairment of glutathione homeostasis in a yeast model of Friedreich's ataxia and identify glutathione as a valuable indicator of the redox status of frataxin-deficient cells.
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PMID:Glutathione-dependent redox status of frataxin-deficient cells in a yeast model of Friedreich's ataxia. 1856 74

Friedreich's ataxia (FRDA) is an autosomal recessive disorder caused by mutations in the gene encoding frataxin, a mitochondrial protein implicated in iron metabolism. Current evidence suggests that loss of frataxin causes iron overload in tissues, and increase in free-radical production leading to oxidation and inactivation of mitochondrial respiratory chain enzymes, particularly Complexes I, II, III and aconitase. Glutathione plays an important role in the detoxification of ROS in the Central Nervous System (CNS), where it also provides regulation of protein function by glutathionylation. The cytoskeletal proteins are particularly susceptible to oxidation and appear constitutively glutathionylated in the human CNS. Previously, we showed loss of cytoskeletal organization in fibroblasts of patients with FRDA found to be associated with increased levels of glutathione bound to cytoskeletal proteins. In this study, we analysed the glutathionylation of proteins in the spinal cord of patients with FRDA and the distribution of tubulin and neurofilaments in the same area. We found, for the first time, a significant rise of the dynamic pool of tubulin as well as abnormal distribution of the phosphorylated forms of human neurofilaments in FRDA motor neurons. In the same cells, the cytoskeletal abnormalities co-localized with an increase in protein glutathionylation and the mitochondrial proteins were normally expressed by immunocytochemistry. Our results suggest that in FRDA oxidative stress causes abnormally increased protein glutathionylation leading to prominent abnormalities of the neuronal cytoskeleton.
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PMID:Friedreich's ataxia: oxidative stress and cytoskeletal abnormalities. 1974 29