Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A-to-I RNA editing modifies a variety of biologically important mRNAs, and is specifically catalyzed by either adenosine deaminase acting on RNA type 1 (ADAR1) or type 2 (ADAR2) in mammals including human. Recently several novel A-to-I editing sites were identified in mRNAs abundantly expressed in mammalian organs by means of computational genomic analysis, but which enzyme catalyzes these editing sites has not been determined. Using RNA interference (RNAi) knockdowns, we found that cytoplasmic fragile X mental retardation protein interacting protein 2 (CYFIP2) mRNA had an ADAR2-mediated editing position and bladder cancer associated protein (BLCAP) mRNA had an ADAR1-mediated editing position. In addition, we found that ADAR2 forms a complex with mRNAs with ADAR2-mediated editing positions including GluR2, kv1.1 and CYFIP2 mRNAs, particularly when the editing sites were edited in human cerebellum by means of immunoprecipitation (IP) method. CYFIP2 mRNA was ubiquitously expressed in human tissues with variable extents of K/E site editing. Because ADAR2 underactivity may be a causative molecular change of death of motor neurons in sporadic amyotrophic lateral sclerosis (ALS), this newly identified ADAR2-mediated editing position may become a useful tool for ALS research.
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PMID:Determination of editors at the novel A-to-I editing positions. 1840 64

Marked reduction of RNA editing at the glutamine (Q)/arginine (R) site of the glutamate receptor subunit type 2 (GluR2) in motor neurons may be a contributory cause of neuronal death specifically in sporadic ALS. It has been shown that deregulation of RNA editing of several mRNAs plays a causative role in diseases of the central nervous system such as depression. We analyzed the effects of eight antidepressants on GluR2 Q/R site-RNA editing in a modified HeLa cell line that stably expresses half-edited GluR2 pre-mRNA. We also measured changes in RNA expression levels of adenosine deaminase acting on RNA type 2 (ADAR2), the specific RNA editing enzyme of the GluR2 Q/R site, and GluR2, in order to assess the molecular mechanism causing alteration of this site-editing. The editing efficiency at the GluR2 Q/R site was significantly increased after treatment with seven out of eight antidepressants at a concentration of no more than 10 microM for 24h. The relative abundance of ADAR2 mRNA to GluR2 pre-mRNA or to beta-actin mRNA was increased after treatment with six of the effective antidepressants, whereas it was unchanged after treatment with milnacipran. Our results suggest that antidepressants have the potency to enhance GluR2 Q/R site-editing by either upregulating the ADAR2 mRNA expression level or other unidentified mechanisms. It may be worth investigating the in vivo efficacy of antidepressants with a specific therapeutic strategy for sporadic ALS in view.
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PMID:Effects of antidepressants on GluR2 Q/R site-RNA editing in modified HeLa cell line. 1944 93

alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor-mediated excitotoxicity has been proposed to play a role in death of motor neurons in amyotrophic lateral sclerosis (ALS). We demonstrated that RNA editing of GluR2 mRNA at the glutamine/arginine (Q/R) site was decreased in autopsy-obtained spinal motor neurons, but not in cerebellar Purkinje cells, of patients with sporadic ALS. This molecular change occurs in motor neurons of sporadic ALS cases with various phenotypes, but not in degenerating neurons of patients with other neurodegenerative diseases, including SOD1-associated familial ALS. Because GluR2 Q/R site-editing is specifically catalyzed by adenosine deaminase acting on RNA 2 (ADAR2), it is likely that regulatory mechanism of ADAR2 activity does not work well in the motor neurons of sporadic ALS. Indeed, ADAR2 expression level was significantly decreased in the spinal ventral gray matter of sporadic ALS as compared to normal control subjects. It is likely that ADAR2 underactivity selective in motor neurons induced deficient GluR2 Q/R site-editing, which results in the neuronal death of sporadic ALS. Thus, among multiple different molecular mechanisms underlying death of motor neurons, it is likely that an increase of the proportion of Q/R site-unedited GluR2-containing Ca(2+)-permeable AMPA receptors initiates the death of motor neurons in sporadic ALS. To this end, normalization of ADAR2 activity in motor neurons may become a therapeutic strategy for sporadic ALS.
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PMID:AMPA receptor-mediated neuronal death in sporadic ALS. 2010 21

Both the appearance of cytoplasmic inclusions containing phosphorylated TAR DNA-binding protein (TDP-43) and inefficient RNA editing at the GluR2 Q/R site are molecular abnormalities observed specifically in motor neurons of patients with sporadic amyotrophic lateral sclerosis (ALS). The purpose of this study is to determine whether a link exists between these two specific molecular changes in ALS spinal motor neurons. We immunohistochemically examined the expression of adenosine deaminase acting on RNA 2 (ADAR2), the enzyme that specifically catalyzes GluR2 Q/R site-editing, and the expression of phosphorylated and non-phosphorylated TDP-43 in the spinal motor neurons of patients with sporadic ALS. We found that all motor neurons were ADAR2-positive in the control cases, whereas more than half of them were ADAR2-negative in the ALS cases. All ADAR2-negative neurons had cytoplasmic inclusions that were immunoreactive to phosphorylated TDP-43, but lacked non-phosphorylated TDP-43 in the nucleus. Our results suggest a molecular link between reduced ADAR2 activity and TDP-43 pathology.
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PMID:TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2. 2037 15

The motor neurons of patients with sporadic amyotrophic lateral sclerosis (ALS) express abundant Q/R site-unedited GluR2 mRNA, whereas those of patients with other motor neuron diseases including familial ALS associated with mutated SOD1 (ALS1) and those of normal subjects express only Q/R site-edited GluR2 mRNA. Because adenosine deaminase acting on RNA type 2 (ADAR2) specifically catalyzes GluR2 Q/R site-editing, it is likely that ADAR2 activity is not sufficient to edit this site completely in motor neurons of patients with sporadic ALS. Because these molecular abnormalities occur in disease- and motor neuron-specific fashion and induce fatal epilepsy in mice, we have hypothesized that GluR2 Q/R site-underediting due to ADAR2 underactivity is a cause of neuronal death in sporadic ALS. We found that cytoplasmic fragile X mental retardation protein interacting protein 2 (CYFIP2) mRNA had an ADAR2-mediated editing position using RNA interference knockdown. Our review will include a discussion of new ADAR2 substrates that may be useful for research on sporadic ALS.
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PMID:Novel etiological and therapeutic strategies for neurodiseases: RNA editing enzyme abnormality in sporadic amyotrophic lateral sclerosis. 2042 86

GluR2 is a subunit of the AMPA receptor, and the adenosine for the Q/R site of its pre-mRNA is converted to inosine (A-to-I conversion) by the enzyme called adenosine deaminase acting on RNA 2 (ADAR2). Failure of A-to-I conversion at this site affects multiple AMPA receptor properties, including the Ca(2+) permeability of the receptor-coupled ion channel, thereby inducing fatal epilepsy in mice (Brusa et al., 1995; Feldmeyer et al., 1999). In addition, inefficient GluR2 Q/R site editing is a disease-specific molecular dysfunction found in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients (Kawahara et al., 2004). Here, we generated genetically modified mice (designated as AR2) in which the ADAR2 gene was conditionally targeted in motor neurons using the Cre/loxP system. These AR2 mice showed a decline in motor function commensurate with the slow death of ADAR2-deficient motor neurons in the spinal cord and cranial motor nerve nuclei. Notably, neurons in nuclei of oculomotor nerves, which often escape degeneration in ALS, were not decreased in number despite a significant decrease in GluR2 Q/R site editing. All cellular and phenotypic changes in AR2 mice were prevented when the mice carried endogenous GluR2 alleles engineered to express edited GluR2 without ADAR2 activity (Higuchi et al., 2000). Thus, loss of ADAR2 activity causes AMPA receptor-mediated death of motor neurons.
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PMID:Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. 2222 19

AMPA receptors are glutamate receptors that are tetramers of various combinations of GluR1-4 subunits. AMPA receptors containing GluR1, 3 and 4 are Ca2+ permeable, however, AMPA receptors containing even a single subunit of GluR2 are Ca2+ impermeable. Most AMPA receptors are Ca2+ impermeable due to the presence of GluR2. GluR2 confers special properties on AMPA receptors through the presence of arginine at the pore apex; other subunits (GluR1, 3, 4) contain glutamine at the pore apex and allow Ca2+ influx. Normally, an RNA editing step changes DNA-encoded glutamine to arginine, introduces arginine in the GluR2 pore apex. GluR2 RNA editing is carried out by an RNA-dependent adenosine deaminase (ADAR2). Loss of GluR2 editing leads to the formation of highly excitotoxic AMPA channels [Mahajan and Ziff (2007) Mol Cell Neurosci 35:470-481] and is shown to contribute to loss of motor neurons in amyotrophic lateral sclerosis (ALS). Relatively higher levels of Ca2+-permeable AMPA receptors are found in motor neurons and this has been correlated with lower GluR2 mRNA levels. However, the reason for loss of GluR2 editing is not known. Here we show that exposure of neurons to excitotoxic levels of glutamate leads to specific cleavage of ADAR2 that leads to generation of unedited GluR2. We demonstrate that cleaved ADAR2 leads to a decrease or loss of GluR2 editing, which will further result in high Ca2+ influx and excitotoxic neuronal death.
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PMID:Exposure of neurons to excitotoxic levels of glutamate induces cleavage of the RNA editing enzyme, adenosine deaminase acting on RNA 2, and loss of GLUR2 editing. 2162 Sep 33

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. More than 90% of ALS cases are sporadic, and the majority of sporadic ALS patients do not carry mutations in genes causative of familial ALS; therefore, investigation specifically targeting sporadic ALS is needed to discover the pathogenesis. The motor neurons of sporadic ALS patients express unedited GluA2 mRNA at the Q/R site in a disease-specific and motor neuron-selective manner. GluA2 is a subunit of the AMPA receptor, and it has a regulatory role in the Ca(2+)-permeability of the AMPA receptor after the genomic Q codon is replaced with the R codon in mRNA by adenosine-inosine conversion, which is mediated by adenosine deaminase acting on RNA 2 (ADAR2). Therefore, ADAR2 activity may not be sufficient to edit all GluA2 mRNA expressed in the motor neurons of ALS patients. To investigate whether deficient ADAR2 activity plays pathogenic roles in sporadic ALS, we generated genetically modified mice (AR2) in which the ADAR2 gene was conditionally knocked out in the motor neurons. AR2 mice showed an ALS-like phenotype with the death of ADAR2-lacking motor neurons. Notably, the motor neurons deficient in ADAR2 survived when they expressed only edited GluA2 in AR2/GluR-B(R/R) (AR2res) mice, in which the endogenous GluA2 alleles were replaced by the GluR-B(R) allele that encoded edited GluA2. In heterozygous AR2 mice with only one ADAR2 allele, approximately 20% of the spinal motor neurons expressed unedited GluA2 and underwent degeneration, indicating that half-normal ADAR2 activity is not sufficient to edit all GluA2 expressed in motor neurons. It is likely therefore that the expression of unedited GluA2 causes the death of motor neurons in sporadic ALS. We hypothesize that a progressive downregulation of ADAR2 activity plays a critical role in the pathogenesis of sporadic ALS and that the pathological process commences when motor neurons express unedited GluA2.
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PMID:When Does ALS Start? ADAR2-GluA2 Hypothesis for the Etiology of Sporadic ALS. 2210 33

TDP-43 pathology in motor neurons is a hallmark of ALS. In addition, the reduced expression of an RNA editing enzyme, adenosine deaminase acting on RNA 2 (ADAR2), increases the expression of GluA2 with an unedited Q/R site in the motor neurons of patients with sporadic ALS. As the occurrence of these two disease-specific abnormalities in the same motor neurons suggests a molecular link between them, we examined the effects of altered TDP-43 processing on ADAR2 activity in TetHeLaG2m and Neuro2a cells. We found that ADAR2 activity did not consistently change due to the overexpression or knockdown of TDP-43 or the expression of abnormal TDP-43, including caspase-3-cleaved fragments, truncated TDP-43 lacking either nuclear localization or export signals and ALS-linked TDP-43 mutants. These results suggest that the abnormal processing of TDP-43 is not an upstream event of inefficient GluA2 Q/R site editing in the motor neurons of sporadic ALS patients.
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PMID:The abnormal processing of TDP-43 is not an upstream event of reduced ADAR2 activity in ALS motor neurons. 2241 30

The motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients exhibit several molecular abnormalities, including 2 that are specific to ALS motor neurons: (1) pathological changes related to the mislocalization of the TAR DNA-binding protein (TDP-43), including both the appearance of phosphorylated TDP-43-containing inclusions in the cytoplasm and the loss of TDP-43 from the nucleus; and (2) inefficient RNA editing at the Q/R site of GluA2, a subunit of the AMPA receptor. TDP-43-related pathological features are closely associated with ALS in most ALS patients and with significant behavioral and pathological changes in genetically engineered mice; therefore, abnormal TDP-43 processing is believed to play a role in the pathogenesis of ALS. The extent of GluA2 RNA editing decreases in the motor neurons of sporadic ALS patients in a disease-specific and motor neuron-selective manner. Importantly, this molecular abnormality is a direct cause of death of motor neurons in conditional knockout mice for adenosine deaminase acting on RNA 2 (ADAR2), the enzyme that specifically catalyzes RNA editing at the GluA2 Q/R site. Notably, these molecular abnormalities, i.e., TDP-43-related pathological features and inefficient GluA2 RNA editing, are found in approximately half of the motor neurons in sporadic ALS patients and both of them always occur in the same motor neurons. Because TDP-43-related pathological features and inefficient GluA2 RNA editing are highly disease specific in ALS motor neurons, investigation into the molecular link between these abnormalities is likely to provide new insights into ALS pathogenesis.
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PMID:[Molecular link between inefficient GluA2 RNA editing and TDP-43 pathology in ALS motor neurons]. 2257 68


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