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)

We have investigated electron transfer activities of respiratory chain complexes in platelet mitochondria of a patient with intermittent ataxia and lactic acidosis who was previously reported to be deficient in the E1 (decarboxylase) component of the pyruvate dehydrogenase complex. Electron transfer from succinate to cytochrome c was normal, but the mitochondria exhibited moderately decreased (63% of control) quinol: cytochrome-c oxidoreductase activity, suggesting a defect in complex III. Consistent with some perturbation in complex III, electron flux through complex III was resistant to inhibition by myxothiazol compared to normal controls. In contrast, titration with antimycin revealed a less abnormal pattern of inhibition. The extreme specificity of myxothiazol binding at or near the quinol oxidase domain of mitochondrial cytochrome b, i.e., b-566, suggests a defect in this region of complex III which may perturb the kinetics or thermodynamics of quinol oxidation in the complex. These data suggest that the patient's illness results from a mutation in the quinol oxidase domain of mitochondrial cytochrome b (b-566).
 ...
PMID:Myxothiazol resistance in human mitochondria. 284 49

Interactions between the checkpoint abrogator UCN-01 and several pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway have been examined in a variety of human leukemia cell lines. Exposure of U937 monocytic leukemia cells to a marginally toxic concentration of UCN-01 (e.g., 150 nM) for 18 h resulted in phosphorylation/activation of p42/44 MAPK. Coadministration of the MEK inhibitor PD184352 (10 microM) blocked UCN-01-induced MAPK activation and was accompanied by marked mitochondrial damage (e.g., cytochrome c release and loss of DeltaPsi(m)), caspase activation, DNA fragmentation, and apoptosis. Similar interactions were noted in the case of other MEK inhibitors (e.g., PD98059; U0126) as well as in multiple other leukemia cell types (e.g., HL-60, Jurkat, CCRF-CEM, and Raji). Coadministration of PD184352 and UCN-01 resulted in reduced binding of the cdc25C phosphatase to 14-3-3 proteins, enhanced dephosphorylation/activation of p34(cdc2), and diminished phosphorylation of cyclic AMP-responsive element binding protein. The ability of UCN-01, when combined with PD184352, to antagonize cdc25C/14-3-3 protein binding, promote dephosphorylation of p34(cdc2), and potentiate apoptosis was mimicked by the ataxia telangectasia mutation inhibitor caffeine. In contrast, cotreatment of cells with UCN-01 and PD184352 did not substantially increase c-Jun-NH(2)-terminal kinase activation nor did it alter expression of Bcl-2, Bcl-x(L), Bax, or X-inhibitor of apoptosis. However, coexposure of U937 cells to UCN-01 and PD184352 induced a marked increase in p38 MAPK activation. Moreover, SB203580, which inhibits multiple kinases including p38 MAPK, partially antagonized cell death. Lastly, although UCN-01 +/- PD184352 did not induce p21(CIP1), stable expression of a p21(CIP1) antisense construct significantly increased susceptibility to this drug combination. Together, these findings indicate that exposure of leukemic cells to UCN-01 leads to activation of the MAPK cascade and that interruption of this process by MEK inhibition triggers perturbations in several signaling and cell cycle regulatory pathways that culminate in mitochondrial injury, caspase activation, and apoptosis. They also raise the possibility that disrupting multiple signaling pathways, e.g., by combining UCN-01 with MEK inhibitors, may represent a novel antileukemic strategy.
 ...
PMID:Pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase/MAPK cascade interact synergistically with UCN-01 to induce mitochondrial dysfunction and apoptosis in human leukemia cells. 1143 48

A 31-year-old woman had encephalopathy, growth retardation, infantilism, ataxia, deafness, lactic acidosis, and increased signals of caudate and putamen on brain magnetic resonance imaging. Muscle biochemistry showed succinate:cytochrome c oxidoreductase (complex II-III) deficiency. Both clinical and biochemical abnormalities improved remarkably with coenzyme Q10 supplementation. Clinically, when taking 300mg coenzyme Q10 per day, she resumed walking, gained weight, underwent puberty, and grew 20cm between 24 and 29 years of age. Coenzyme Q10 was markedly decreased in cerebrospinal fluid, muscle, lymphoblasts, and fibroblasts, suggesting the diagnosis of primary coenzyme Q10 deficiency. An older sister has similar clinical course and biochemical abnormalities. These findings suggest that coenzyme Q10 deficiency can present as adult Leigh's syndrome.
 ...
PMID:Coenzyme Q-responsive Leigh's encephalopathy in two sisters. 1244 28

We describe a young woman with a progressive mitochondrial myopathy that started with muscle weakness and went on to include deafness, dementia and ataxia. Skeletal muscle showed the histological and biochemical features of mitochondrial respiratory chain dysfunction. Genetic analysis identified a novel, heteroplasmic, A to G transition in tRNA(Ser(UCN)) at position 7480 affecting a highly conserved base in the anticodon loop. Single-fibre PCR showed highest levels of mutation in cytochrome c-oxidase-deficient fibres and quantification in two biopsies taken 5 years apart showed no change in percentage heteroplasmy. The mutation was present at lower levels in the patient's blood, but was not found in either her mother's or sister's blood and skeletal muscle, suggesting a sporadic occurrence. This is the eighth disease-causing mutation in this tRNA gene and confirms serine (UCN) as one of the most common sites for mtDNA mutation.
 ...
PMID:Sporadic mitochondrial myopathy due to a new mutation in the mitochondrial tRNASer(UCN) gene. 1521 Jan 64

The Kearns-Sayre syndrome, (characterized by its onset before the age of 20 years, chronic ophthalmoplegia, pigmentary retinal degeneration and at least one of the following symptoms: ataxia, heart block and high protein content in the cerebrospinal fluid) is a severe variant of chronic progressive external ophthalmoplegia with frequent rearrangements of the mitochondrial DNA (mtDNA). The aim of this paper is to report a sporadic paediatric case of Kearns-Sayre syndrome with mtDNA heteroplasmic deletion, absence of cytochrome c-oxidase in many muscle fibers, autoimmune thyroiditis, complete atrio-ventricular heart block in which the diagnosis of subclinical hypothyroiditis associated with autoimmune thyroid disease was made. The subclinical hypothyroidism, more severe in the presence of thyroid antibodies, may have contributed to the pathogenesis of cardiovascular disease. We hypothesized that in this patient, predisposed by mitochondrial deletion, anti-thyroid antibodies may have interfered with the mitochondrial function of conduction heart system, causing atrio-ventricular heart block. It seems important to study anti-thyroid antibodies in every case of Kearn-Sayre syndrome, specially if cardiac rhythm disturbances are present.
 ...
PMID:A case of Kearns-Sayre sindrome with autoimmune thyroiditis and complete atrio-ventricular block. 1673 14

Mitochondria are involved in hematopoietic cell homeostasis through multiple ways such as oxidative phosphorylation, various metabolic processes and the release of cytochrome c in the cytosol to trigger caspase activation and cell death. In erythroid cells, the mitochondrial steps in heme synthesis, iron (Fe) metabolism and Fe-sulfur (Fe-S) cluster biogenesis are of particular importance. Mutations in the specific delta-aminolevulinic acid synthase (ALAS) 2 isoform that catalyses the first and rate-limiting step in heme synthesis pathway in the mitochondrial matrix, lead to ineffective erythropoiesis that characterizes X-linked sideroblastic anemia (XLSA), the most common inherited sideroblastic anemia. Mutations in the adenosine triphosphate-binding cassette protein ABCB7, identified in XLSA with ataxia (XLSA-A), disrupt the maturation of cytosolic (Fe-S) clusters, leading to mitochondrial Fe accumulation. In addition, large deletions in mitochondrial DNA, whose integrity depends on a specific DNA polymerase, are the hallmark of Pearson's syndrome, a rare congenital disorder with sideroblastic anemia. In acquired myelodysplastic syndromes at early stage, exacerbation of physiological pathways involving caspases and the mitochondria in erythroid differentiation leads to abnormal activation of a mitochondria-mediated apoptotic cell death pathway. In contrast, oncogenesis-associated changes at the mitochondrial level can alter the apoptotic response of transformed hematopoietic cells to chemotherapeutic agents. Recent findings in mitochondria metabolism and functions open new perspectives in treating hematopoietic cell diseases, for example various compounds currently developed to trigger tumor cell death by directly targeting the mitochondria could prove efficient as either cytotoxic drugs or chemosensitizing agents in treating hematological malignancies.
 ...
PMID:Mitochondria in hematopoiesis and hematological diseases. 1689 88

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

We describe a patient with acute combined demyelinating disease of the central and peripheral nervous systems associated with the A8344G mutation in the mitochondrial tRNA lysine gene. A 7-year-old boy presented with acute onset of palpitations, tinnitus, ataxia, bilateral sixth nerve palsy, and flaccid quadriparesis. Serum creatine kinase and lactate were mildly increased. Electromyography showed demyelinating sensory and motor polyneuropathy. Brain magnetic resonance imaging demonstrated demyelination in the left thalamus and magnetic resonance spectroscopy revealed a lactate peak corresponding to this lesion. Histologic analysis of the muscle showed cytochrome c-oxidase-deficient fibers and ragged red fibers. Respiratory chain analyses revealed deficiencies of complexes I and IV. Molecular genetic analyses of the muscle showed an A8344G (MERRF) mutation in mitochondrial tRNA lysine. To the best of our knowledge, this is the first description of this mutation associated with acute combined demyelinating disease of the central and peripheral nervous systems.
 ...
PMID:Demyelinating disease of central and peripheral nervous systems associated with a A8344G mutation in tRNALys. 1926 23

Multiple system atrophy (MSA) is an adult-onset sporadic neurodegenerative disorder of unknown etiology featuring parkinsonism, ataxia, and autonomic failure in any combination. Because disease progression in MSA is rapid and no drug treatment consistently benefits MSA patients in the long term, neuroprotective or regenerative strategies may be invaluable in the management of MSA patients. In this study, we investigated whether human mesenchymal stem cells (hMSCs) had a protective effect on MSA using an animal model of double-toxin-induced MSA parkinsonism (MSA-P). MSA-P was established with coinjections of MPTP and 3-NP; hMSCs were injected into the tail vein 1 day after the last toxin injection. Three groups of mice were compared (i.e., control, MPTP + 3-NP, and MPTP + 3-NP with hMSC treatment) through histopathological, behavioral, and Western blot analyses. In the substantia nigra (SN) and the striatum, 2.0% and 3.8% of total injected hMSCs were observed, respectively. Compared with double-toxin-treated mice, hMSC treatment in double-toxin-treated mice significantly increased survival of TH- and NeuN-immunoreactive cells in the SN and the striatum, with coincident improvement in motor behavior. Additionally, hMSC treatment significantly decreased double-toxin-induced microglial and astroglial activation in the SN and striatum. Western blot analysis showed that hMSC administration in double-toxin-treated mice increased the expression of p-Akt and Bcl-2 and decreased Bax and cytochrome c expression. This study demonstrates that hMSC treatment protected against loss of neurons in the SN and the striatum induced by double toxin exposure, which may be mediated by modulation of inflammatory and cell survival and death signaling-pathway as the hMSCs migrated from the peripheral circulation into the SN and striatum.
 ...
PMID:Neuroprotective effect of human mesenchymal stem cells in an animal model of double toxin-induced multiple system atrophy parkinsonism. 2105 46

The mitochondrial respiratory chain complex IV (cytochrome c oxidase) is a multi-subunit enzyme that transfers electrons from cytochrome c to molecular oxygen, yielding water. Its biogenesis requires concerted expression of mitochondria- and nuclear-encoded subunits and assembly factors. In this report, we describe a homozygous missense mutation in FAM36A from a patient who displays ataxia and muscle hypotonia. The FAM36A gene is a remote, putative ortholog of the fungal complex IV assembly factor COX20. Messenger RNA (mRNA) and protein co-expression analyses support the involvement of FAM36A in complex IV function in mammals. The c.154A>C mutation in the FAM36A gene, a mutation that is absent in sequenced exomes, leads to a reduced activity and lower levels of complex IV and its protein subunits. The FAM36A protein is nearly absent in patient's fibroblasts. Cells affected by the mutation accumulate subassemblies of complex IV that contain COX1 but are almost devoid of COX2 protein. We observe co-purification of FAM36A and COX2 proteins, supporting that the FAM36A defect hampers the early step of complex IV assembly at the incorporation of the COX2 subunit. Lentiviral complementation of patient's fibroblasts with wild-type FAM36A increases the complex IV activity as well as the amount of holocomplex IV and of individual subunits. These results establish the function of the human gene FAM36A/COX20 in complex IV assembly and support a causal role of the gene in complex IV deficiency.
 ...
PMID:A mutation in the FAM36A gene, the human ortholog of COX20, impairs cytochrome c oxidase assembly and is associated with ataxia and muscle hypotonia. 2312 84


1 2 Next >>