Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BC200 RNA is a polyadenylated 200 nucleotide primate brain-specific transcript with 80% homology to the left monomer of the human Alu family of repetitive elements. Whether this transcription product contributes anything to normal brain gene function or is a residue of post transcriptional processing of brain heterogeneous nuclear RNA (hnRNA) is uncertain. However, the high abundance, tissue-specific expression and nucleotide sequence characteristics of BC200 RNA suggests that the generation of this small RNA is associated with some brain cell function. Sustained levels of the BC200 RNA transcript may be indicative of a genetically competent and normally functioning cerebral neocortex. In this investigation, we have measured the abundance of the BC200 RNA transcript in total RNA isolated from 18 temporal neocortices (Brodman area 22) of brains with no pathology and those affected with neurodegenerative disease. Neocortices were examined from 3 neurologically normal brains, 5 non-Alzheimer demented [NAD; 3 Huntington's chorea (HC), 1 amyotrophic lateral sclerosis (ALS) and 1 dementia unclassified] and 10 Alzheimer disease (AD) affected brains. Our results indicate a strong BC200 presence in both the normal brains and NAD affected neocortices, but a 70 per cent reduction in BC200 signal strength in AD afflicted brains. These results may be related to the observation that Alzheimer brains exhibit marked deficits in the abundance of neuron-specific DNA transcripts; these deficits are consistent with the idea that AD is characterized by an impairment in the primary generation of brain gene transcription products.
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PMID:BC200 RNA in normal human neocortex, non-Alzheimer dementia (NAD), and senile dementia of the Alzheimer type (AD). 160 65

Four enzyme activities related to glucose metabolism, i.e. those of glucose-6-phosphate dehydrogenase (G6PDH; EC 1.1.1.49), lactic dehydrogenase (LDH; EC 1.1.1.27), pyruvate dehydrogenase complex (PDC) and citrate synthase (CS; EC 4.1.3.7) were estimated in posterior root ganglion cells (PRGCs) of the spinal cord in patients suffering from olivopontocerebellar atrophy (OPCA), amyotrophic lateral sclerosis (ALS), and Duchenne muscular dystrophy (DMD) by means of the NAD, NADP and CoA cycling methods. In ALS and DMD, the enzyme activities examined were within normal ranges. In OPCA, PDC activity was significantly reduced and LDH activity tended to be lower than that in controls.
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PMID:Enzymatic analysis of individual posterior root ganglion cells in olivopontocerebellar atrophy, amyotrophic lateral sclerosis and Duchenne muscular dystrophy. 404 97

In skeletal muscle homogenates of 14 patients with sporadic amyotrophic lateral sclerosis, an approximately twofold lower specific activity of NADH:CoQ oxidoreductase in comparison to an age matched control group (n=28) was detected. This finding was confirmed by a detailed analysis of mitochondrial oxidative phosphorylation in skeletal muscle using saponin-permeabilized muscle fibers. (i) A significantly lowered maximal glutamate+malate and pyruvate+malate supported respiration of saponin-permeabilized fibers was detected in the patients group. (ii) Titrations with the specific inhibitor of NADH:CoQ oxidoreductase amytal revealed a higher sensitivity of respiration to this inhibitor indicating an elevated flux control coefficient of this enzyme. (iii) Applying functional imaging of mitochondria using ratios of NAD(P)H and flavoprotein autofluorescence images of saponin-permeabilized fibers we detected the presence of partially respiratory chain inhibited mitochondria on the single fiber level. A secondary defect of mitochondrial function due to the neurogenic changes in muscle seems to be unlikely since no mitochondrial abnormalities were detectable in biopsies of patients with spinal muscular atrophy. These results support the viewpoint that an impairment of mitochondria may be of pathophysiological significance in the etiology of amyotrophic lateral sclerosis.
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PMID:Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis. 955 89

In the CNS, reactive oxygen species (ROS) have been implicated in a wide range of degenerative processes including amyotrophic lateral sclerosis, ischemia-reperfusion injury, Alzheimer disease, Parkinson disease and aging. However, the exact mechanism is unknown, and there is little information on possible roles of ROS in cell injury and the process on recovery of astrocytes, the most abundant glial cells in the brain. We examined hydrogen peroxide (H2O2)-induced DNA fragmentation and thymidine incorporation into cultured astrocytes as an indicator of the process of recovery from astrocytic DNA injury. Astrocytes were isolated from cerebral cortices of 0-day-old rats and treated with 1 mM dibutyryl cyclic AMP for 4 days. H2O2 of 100 microM stimulated thymidine incorporation into astrocytes. Caffeine, ryanodine, cyclic ADP-ribose (endogenous ryanodine receptor agonist) and beta-NAD+ (precursor of cyclic ADP-ribose) suppressed partially the stimulatory effect of H2O2. Ruthenium red (ryanodine receptor antagonist) facilitated further the stimulatory effect of H2O2. The facilitated effect of ruthenium red on H2O2-induced thymidine incorporation was suppressed by caffeine, ryanodine, cyclic ADP-ribose and beta-NAD+. H2O2-induced DNA fragmentation and astrocytic death were suppressed by ruthenium red. These findings suggest that the process of recovery from astrocytic DNA injury by H2O2 may be regulated by Ca2+ efflux from ryanodine-sensitive intracellular Ca2+ stores.
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PMID:[Role of ryanodine receptors in hydrogen peroxide-induced DNA fragmentation and thymidine incorporation in cultured rat astrocytes]. 1019 Jan 45

The mitochondrial function in skeletal muscle was investigated in skeletal muscle biopsies of 26 patients with sporadic amyotrophic lateral sclerosis (ALS) and compared with investigations of 28 age-matched control muscle samples and biopsies of 6 patients with spinal muscular atrophy (SMA) and two patients with Tay-Sachs disease. In comparison to the control, SMA and Tay-Sachs biopsies, we observed in the ALS samples a significant about two-fold lower activity of complex I of mitochondrial respiratory chain. To visualise the distribution of the mitochondrial defect in skeletal muscle fibers we applied confocal laser-scanning microscopy and video fluorescence microscopy of NAD(P)H and fluorescent flavoproteins. The redox change of mitochondrial NAD(P)H and flavoproteins on addition of mitochondrial substrates, ADP, or cyanide were determined by measurement of fluorescence intensities with dual-photon UV-excitation and single-photon blue excitation. In skeletal muscle fibers of ALS patients with abnormalities of mitochondrial DNA (multiple deletions, n=1, or lower mtDNA levels, n=14) we observed a heterogeneous distribution of the mitochondrial defects among individual fibers and even within single fibers. In some patients (n=3) a mitochondrial defect was also detectable in cultivated skin fibroblasts. These findings support the viewpoint that the observed impairment of mitochondrial function in muscle of certain ALS patients is caused by an intrinsic mitochondrial defect which may be of pathophysiological significance in the etiology of this neurodegenerative disease.
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PMID:Visualization of defective mitochondrial function in skeletal muscle fibers of patients with sporadic amyotrophic lateral sclerosis. 1054 22

Amyotrophic lateral sclerosis is a neurodegenerative disease affecting the anterior horn cells of the spinal cord and cortical motor neurons. Previous findings have suggested a specific impairment of mitochondrial function in skeletal muscle of at least a limited number of patients. Applying flavoprotein/NAD(P)H autofluorescence imaging of mitochondrial function in saponin-permeabilized muscle fibres, we detected a heterogeneous distribution of the respiratory chain defect among individual fibres in muscle biopsies of patients (11 out of 17) with sporadic amyotrophic lateral sclerosis (SALS). These findings correlate with the presence of cytochrome c oxidase (COX)-negative muscle fibres detected histologically. We established the molecular basis for the decreased activities of NADH:CoQ oxidoreductase and COX in SALS muscle. In the skeletal muscle of the investigated patients, diminished levels (13 out of 17) or multiple deletions (one out of 17) of mitochondrial DNA (mtDNA) were observed. These alterations of mtDNA seem to be related to decreased levels of membrane-associated mitochondrial Mn-superoxide dismutase. Our results support the viewpoint that an oxygen radical-induced impairment of mtDNA is of pathophysiological significance in the aetiology of at least a subgroup of patients with SALS.
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PMID:Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. 1086 44

Protein interactions of the Amyotrophic Lateral Sclerosis (ALS)-linked copper-zinc superoxide dismutase (hSOD1) G93A mutation were studied using a fluorescence resonance energy transfer (FRET) based screening system. The FRET results confirmed by pull-down immunoprecipitation indicated "gain-of-interaction" of the G93A-hSOD1 mutant with cytosolic malate dehydrogenase (cytMDH)-a key enzyme in the malate-aspartate shuttle which is vital to neurons. Furthermore, cytMDH mRNA expression was upregulated in G93A-hSOD1 expressing cells but endogenous cytMDH enzymatic activity was not enhanced, not even with exogenously added-on enzyme. Consistent with inhibition of the malate-aspartate shuttle, G93A-hSOD1 had lower malate and higher lactate levels compared to non-induced or Wild-Type-hSOD1 expressing cells. Mitochondrial NADH/NAD+ ratio is also elevated. Malate-aspartate shuttle dysfunction may explain the damage to neurons and the vulnerability to impairments of glycolytic pathways in ALS and provide a new target for the development of potential therapies.
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PMID:Gain of interaction of ALS-linked G93A superoxide dismutase with cytosolic malate dehydrogenase. 1865 97

Reactive oxygen species (ROS) are produced at low levels in mammalian cells by various metabolic processes, such as oxidative phosphorylation by the mitochondrial respiratory chain, NAD(P)H oxidases, and arachidonic acid oxidative metabolism. To maintain physiological redox balance, cells have endogenous antioxidant defenses regulated at the transcriptional level by Nrf2/ARE. Oxidative stress results when ROS production exceeds the cell's ability to detoxify ROS. Overproduction of ROS damages cellular components, including lipids, leading to decline in physiological function and cell death. Reaction of ROS with lipids produces oxidized phospholipids, which give rise to 4-hydroxynonenal, 4-oxo-2-nonenal, and acrolein. The brain is susceptible to oxidative damage due to its high lipid content and oxygen consumption. Neurodegenerative diseases (AD, ALS, bipolar disorder, epilepsy, Friedreich's ataxia, HD, MS, NBIA, NPC, PD, peroxisomal disorders, schizophrenia, Wallerian degeneration, Zellweger syndrome) and CNS traumas (stroke, TBI, SCI) are problems of vast clinical importance. Free iron can react with H(2)O(2) via the Fenton reaction, a primary cause of lipid peroxidation, and may be of particular importance for these CNS injuries and disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Atherosclerosis, the major risk factor for ischemic stroke, involves accumulation of oxidized LDL in the arteries, leading to foam cell formation and plaque development. This review will discuss the role of lipid oxidation/peroxidation in various CNS injuries/disorders.
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PMID:Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. 1962 72

Abnormal mitochondrial function was reported in patients and models for amyotrophic lateral sclerosis (ALS). It is therefore important to set up sensitive tools for the monitoring of active agents that enhance energy metabolism delay onset, and extend lifespan of transgenic G93A-SOD1 ALS mice. In this report, primary motor cortex slices from G93A mice at different stages of disease were studied, using NAD(P)H autofluorescence post-synaptic signals following ultraviolet stimuli, as a probe to evaluate mitochondrial function. We observed consistent age-related alterations of responses in G93A primary motor cortex slices versus controls. We conclude that NAD(P)H autofluorescence post-synaptic signal is a highly sensitive real-time technique to detect mitochondrial function failure in primary cortex from living tissues.
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PMID:Dynamic NAD(P)H post-synaptic autofluorescence signals for the assessment of mitochondrial function in a neurodegenerative disease: monitoring the primary motor cortex of G93A mice, an amyotrophic lateral sclerosis model. 1990 May 86

Various missense mutations were identified in TAR DNA-binding protein-43 (TDP-43) in patients with amyotrophic lateral sclerosis (ALS). To explore the toxic effect of mutant TDP-43, we generated stable transfection of wild-type and mutant TDP-43 in motor neuron-like cell line. We found that mutant TDP-43 induced mitochondrial dysfunction, oxidative damage and nuclear accumulation of nuclear factor E2-related factor 2 (Nrf2). Nrf2 is an indicator and modulator of oxidative stress and is known to promote the expression of phase || detoxification enzyme including heme oxygenase-1 (HO-1). However, HO-1 was down regulated in cells expressing the mutant TDP-43, and could not be restored by sulforaphane which is a known stimulator of Nrf2 and phase || detoxification enzyme, including HO-1. Nevertheless, sulforaphane reduced the level of lactate dehydrogenase and lipoperoxidation products in cells expressing TDP-43 mutant. However, sulforaphane could upregulate the expression of HO-1 and NAD(P)H/quinone oxidoreductase-1 (NQO-1) in cells transfected with the empty vector and the wild-type TDP-43. Thus, sulforaphane protected cells against mutant TDP-43 independent of Nrf2-antioxidant response element (ARE) pathway. How mutant TDP-43 reduces expression of HO-1 and prevents sulforaphane from activating Nrf2 signaling remains to be investigated.
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PMID:Mutant TAR DNA-binding protein-43 induces oxidative injury in motor neuron-like cell. 2060 Jun 71


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