Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to obtain information on the mechanisms of neurotoxicity of 1,1,1-trichloroethane, rats maintained artificially ventilated on N2O:O2 (70:30) were exposed to a concentration of 1,1,1-trichloroethane of 8000 ppm, 43.7 mg L-1, that induces moderate ataxia in awake, spontaneously breathing animals. After 5 and 60 min of exposure, as well as after a 60-min recovery period following 60 min of exposure, the brain was frozen in situ and cortical tissue was assayed for phosphocreatine (PCr), + ATP, ADP, AMP, glycogen, glucose, pyruvate, lactate, citric acid cycle intermediates, associated amino acids, and cyclic nucleotides; in addition, purine nucleotides, nucleosides, and bases were assayed by HPLC techniques. Exposure of animals to 1,1,1-trichloroethane failed to alter blood glucose, lactate, and pyruvate concentrations. However, the solvent induced highly significant increases in tissue lactate and pyruvate concentrations that were also reflected in cisternal CSF. Associated with these changes were increases in all citric acid cycle intermediates except succinate, an increase in alanine concentration, and a rise in the glutamate/aspartate ratio. After 5 min, a small decrease in glycogen concentration also occurred. All these changes were reversed when the exposure was terminated. No changes were observed in tissue concentrations of purine nucleotides, nucleosides, and bases except for a small reduction of ATP concentration after 60 min of exposure, still noticeable after 60 min of recovery. Apart from a small reduction in cAMP concentration after 5 min of exposure, cyclic nucleotide concentrations did not change.
 ...
PMID:Cerebral metabolic and circulatory effects of 1,1,1-trichloroethane, a neurotoxic industrial solvent. 2. Tissue concentrations of labile phosphates, glycolytic metabolites, citric acid cycle intermediates, amino acids, and cyclic nucleotides. 653 82

Phosphorus magnetic resonance spectroscopy (31P-MRS) was used to study in vivo the energy metabolism of brain and skeletal muscle in two members of an Italian pedigree with NARP syndrome due to a point mutation at bp 8993 of mtDNA. In the youngest patient, a 13 year old girl with retinitis pigmentosa, ataxia, and psychomotor retardation, there was an alteration of brain energy metabolism shown by a decreased phosphocreatine content, increased [ADP] and decreased phosphorylation potential. The energy metabolism of her skeletal muscle was also abnormal, as shown by resting higher inorganic phosphate and lower phosphocreatine concentrations than in normal subjects. Her mother, a 41 year old woman with minimal clinical involvement, showed a milder derangement of brain energy metabolism and normal skeletal muscle. Findings with MRS showed that this point mutation of mtDNA is responsible for a derangement of energy metabolism in skeletal muscle and even more so in the brain.
 ...
PMID:Brain and muscle energy metabolism studied in vivo by 31P-magnetic resonance spectroscopy in NARP syndrome. 779 79

Ionizing radiation activates not only signalling pathways in the nucleus as a result of DNA damage, but also signalling pathways initiated at the level of the plasma membrane. Proteins involved in DNA damage recognition include poly(ADP ribose) polymerase (PARP), DNA-dependent protein kinase, p53 and ataxia- telangiectasia mutated (ATM). Many of these proteins are inactivated by caspases during the execution phase of apoptosis. Signalling pathways outside the nucleus involve tyrosine kinases such as stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), protein kinase C, ceramide and reactive oxygen species. Recent evidence shows that tumour cells resistant to ionizing radiation-induced apoptosis have defective ceramide signalling. How these signalling pathways converge to activate the caspases is presently unknown, although in some cell types a role for calpain has been suggested.
 ...
PMID:Molecular mechanisms of ionizing radiation-induced apoptosis. 1036 Dec 59

Molecular biological studies confirmed that two glutamate dehydrogenase isozymes (hGDH1 and hGDH2) of distinct genetic origin are expressed in human tissues. hGDH1 is heat-stable and expressed widely, whereas hGDH2 is heat-labile and specific for neural and testicular tissues. A selective deficiency of hGDH2 has been reported in patients with spinocerebellar ataxia. We have identified an amino acid residue involved in the different thermal stability of human GDH isozymes. At 45 degrees C (pH 7.0), heat inactivation proceeded faster for hGDH2 (half life=45 min) than for hGDH1 (half-life=310 min) in the absence of allosteric regulators. Both hGDH1 and hGDH2, however, showed much slower heat inactivation processes in the presence of 1 mM ADP or 3 mM L-Leu. Virtually most of the enzyme activity remained up to 100 min at 45 degrees C after treatment with ADP and L-Leu in combination. In contrast to ADP and L-Leu, the thermal stabilities of the hGDH isozymes were not affected by addition of substrates or coenzymes. In human GDH isozymes, the 443 site is Arg in hGDH1 and Ser in hGDH2. Replacement of Ser by Arg at the 443 site by cassette mutagenesis abolished the heat lability of hGDH2 with a similar half-life of hGDH1. The mutagenesis at several other sites (L415M, A456G, and H470R) having differences in amino acid sequence between the two GDH isozymes did not show any change in the thermal stability. These results suggest that the Ser443 residue plays an important role in the different thermal stability of human GDH isozymes.
 ...
PMID:Important role of Ser443 in different thermal stability of human glutamate dehydrogenase isozymes. 1504 2

Gene expression changes in the lungs induced by paraquat (PQ) administration were studied in rats using DNA microarrays that were detectable for 1,090 genes per DNA microarray. The rats were subjected to subacute PQ exposure (7 mg/kg, s.c., daily for eight administrations). Two days after the final administration, the rats were divided into two groups. Group 1 experienced significant body weight loss and displayed signs of subacute PQ toxicity, but Group 2 showed no significant effects due to the PQ treatment. A control group, Group 3, was also included. In the comparison of the gene expression levels in the animals from Group 1 or Group 2 to the control animals treated by vehicle, 48 genes in Group 1 and 29 genes from Group 2 were differentially expressed. The twenty-eight genes were common to these two groups. These differentially expressed genes following paraquat treatment were classified as follows: 5 neurotransmitter receptor genes; 4 transporter genes; 4 voltage-gated ion channel genes; 2 lipid metabolism enzyme genes; 2 G-proteins involved in endocytosis and exocytosis genes; 7 cytokine genes; 4 ADP ribosylation genes involved in cell death and regeneration; CFTR gene, which is the causal gene for cystic fibrosis; neurofibromatosis type 1 gene, which is the causal gene for the neurofibromatosis type 1 that is known to accompany pulmonary fibrosis; and the causal gene for spinocerebellar ataxia. These genes may prove to be the keys for the elucidation of the mechanism of PQ toxicity, e.g. PQ-induced pulmonary fibrosis.
 ...
PMID:Gene expression analysis of the lung following paraquat administration in rats using DNA microarray. 1520 77

Several different autosomal recessive genetic disorders characterized by ataxia with oculomotor apraxia (AOA) have been identified with the unifying feature of defective DNA damage recognition and/or repair. We describe here the characterization of a novel form of AOA showing increased sensitivity to agents that cause single-strand breaks (SSBs) in DNA but having no gross defect in the repair of these breaks. Evidence for the presence of residual SSBs in DNA was provided by dramatically increased levels of poly (ADP-ribose)polymerase (PARP-1) auto-poly (ADP-ribosyl)ation, the detection of increased levels of reactive oxygen/nitrogen species (ROS/RNS) and oxidative damage to DNA in the patient cells. There was also evidence for oxidative damage to proteins and lipids. Although these cells were hypersensitive to DNA damaging agents, the mode of death was not by apoptosis. These cells were also resistant to TRAIL-induced death. Consistent with these observations, failure to observe a decrease in mitochondrial membrane potential, reduced cytochrome c release and defective apoptosis-inducing factor translocation to the nucleus was observed. Apoptosis resistance and PARP-1 hyperactivation were overcome by incubating the patient's cells with antioxidants. These results provide evidence for a novel form of AOA characterized by sensitivity to DNA damaging agents, oxidative stress, PARP-1 hyperactivation but resistance to apoptosis.
 ...
PMID:A novel form of ataxia oculomotor apraxia characterized by oxidative stress and apoptosis resistance. 1734 66

Aprataxin, defective in the neurodegenerative disorder ataxia oculomotor apraxia type 1 (AOA1), is a DNA repair protein that processes the product of abortive ligations, 5' adenylated DNA. In addition to its interaction with the single-strand break repair protein XRCC1, aprataxin also interacts with poly-ADP ribose polymerase 1 (PARP-1), a key player in the detection of DNA single-strand breaks. Here, we reveal reduced expression of PARP-1, apurinic endonuclease 1 (APE1) and OGG1 in AOA1 cells and demonstrate a requirement for PARP-1 in the recruitment of aprataxin to sites of DNA breaks. While inhibition of PARP activity did not affect aprataxin activity in vitro, it retarded its recruitment to sites of DNA damage in vivo. We also demonstrate the presence of elevated levels of oxidative DNA damage in AOA1 cells coupled with reduced base excision and gap filling repair efficiencies indicative of a synergy between aprataxin, PARP-1, APE-1 and OGG1 in the DNA damage response. These data support both direct and indirect modulating functions for aprataxin on base excision repair.
 ...
PMID:Aprataxin, poly-ADP ribose polymerase 1 (PARP-1) and apurinic endonuclease 1 (APE1) function together to protect the genome against oxidative damage. 1964 12

Mitochondria are subcellular organelles whose major function is to generate energy by coupling through oxidation of nutrient substrates with ATP synthesis, via ADP phosphorylation. This process, known as oxidative phosphorylation, is carried out by the mitochondrial respiratory chain, a pathway consisting of five multi-subunit complexes, four of which take contribution from genes located in two separate compartments, the nuclear chromosomes, and a genome found in mitochondria themselves, mitochondrial DNA (mtDNA). Defects affecting either genome give rise to mitochondrial dysfunction, causing disease that often affects the brain and in particular the cerebellum. Mitochondrial disorders can give rise to pure cerebellar, spinocerebellar, or sensory ataxia, usually as part of a multisystem (and multisymptom) disorder. In this chapter we divide the diseases into those caused by mtDNA defects and those due to mutations involving nuclear genes. With more than 100 mutations in mtDNA and new nuclear genes being described all the time, we have focused on the commonest disorders and used these as examples of the different types of mitochondrial ataxia.
 ...
PMID:Ataxia in mitochondrial disorders. 2182

Poly(ADP)-ribose polymerase (PARP) inhibitors modify the enzymatic activity of PARP1/2. When certain PARP inhibitors are used either alone or in combination with DNA damage agents they may cause a G2/M mitotic arrest and/or apoptosis in a susceptible genetic context. PARP1 interacts with the cell cycle checkpoint proteins Ataxia Telangectasia Mutated (ATM) and ATM and Rad3-related (ATR) and therefore may influence growth arrest cascades. The PARP inhibitor PJ34 causes a mitotic arrest by an unknown mechanism in certain cell lines, therefore we asked whether PJ34 conditionally activated the checkpoint pathways and which downstream targets were necessary for mitotic arrest. We found that PJ34 produced a concentration dependent G2/M mitotic arrest and differentially affected cell survival in cells with diverse genetic backgrounds. p53 was activated and phosphorylated at Serine15 followed by p21 gene activation through both p53-dependent and -independent pathways. The mitotic arrest was caffeine sensitive and UCN01 insensitive and did not absolutely require p53, ATM or Chk1, while p21 was necessary for maintaining the growth arrest. Significantly, by using stable knockdown cell lines, we found that neither PARP1 nor PARP2 was required for any of these effects produced by PJ34. These results raise questions and cautions for evaluating PARP inhibitor effectiveness, suggesting whether effects should be considered not only on PARP's diverse ADP-ribosylation independent protein interactions but also on homologous proteins that may be producing either overlapping or distinct effect.
 ...
PMID:The PARP inhibitor PJ34 causes a PARP1-independent, p21 dependent mitotic arrest. 2184 Feb 68

Mitochondria are highly dynamic organelles that continuously move, fuse and divide. Mitochondrial dynamics modulate overall mitochondrial morphology and are essential for the proper function, maintenance and transmission of mitochondria and mitochondrial DNA (mtDNA). We have investigated mitochondrial fusion in yeast cells with severe defects in oxidative phosphorylation (OXPHOS) due to removal or various specific mutations of mtDNA. We find that, under fermentative conditions, OXPHOS deficient cells maintain normal levels of cellular ATP and ADP but display a reduced mitochondrial inner membrane potential. We demonstrate that, despite metabolic compensation by glycolysis, OXPHOS defects are associated to a selective inhibition of inner but not outer membrane fusion. Fusion inhibition was dominant and hampered the fusion of mutant mitochondria with wild-type mitochondria. Inhibition of inner membrane fusion was not systematically associated to changes of mitochondrial distribution and morphology, nor to changes in the isoform pattern of Mgm1, the major fusion factor of the inner membrane. However, inhibition of inner membrane fusion correlated with specific alterations of mitochondrial ultrastructure, notably with the presence of aligned and unfused inner membranes that are connected to two mitochondrial boundaries. The fusion inhibition observed upon deletion of OXPHOS related genes or upon removal of the entire mtDNA was similar to that observed upon introduction of point mutations in the mitochondrial ATP6 gene that are associated to neurogenic ataxia and retinitis pigmentosa (NARP) or to maternally inherited Leigh Syndrome (MILS) in humans. Our findings indicate that the consequences of mtDNA mutations may not be limited to OXPHOS defects but may also include alterations in mitochondrial fusion. Our results further imply that, in healthy cells, the dominant inhibition of fusion could mediate the exclusion of OXPHOS-deficient mitochondria from the network of functional, fusogenic mitochondria.
 ...
PMID:Mitochondrial DNA mutations provoke dominant inhibition of mitochondrial inner membrane fusion. 2316 36


1 2 Next >>