Underediting of GluR2 mRNA, a neuronal death inducing molecular change in sporadic ALS, does not occur in motor neurons in ALS1 or SBMA

Kawahara, Yukio; Sun, Hui; Ito, Kyoko; Hideyama, Takuto; Akiyama, Masashi; Sobue, Gen; Tsuji, Shoji; Kwak, Shin

doi:10.1016/j.neures.2005.09.006

Cited by 59 publications

(41 citation statements)

References 16 publications

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“…Recently, we demonstrated that a significant proportion of GluR2 mRNA was unedited at the Q/R site in spinal motor neurons of postmortem patients with sporadic ALS. This is in marked contrast to the fact that all GluR2 mRNA was edited in the motor neurons of control subjects (Takuma et al, 1999;Kawahara et al, 2004) and of patients with motor neuron diseases other than sporadic ALS (Kawahara et al, 2006), as well as in dying neurons in other neurodegenerative diseases, including Purkinje cells of patients with spinocerebellar degeneration (Paschen et al, 1994;Akbarian et al, 1995;Kawahara et al, 2004;Suzuki et al, 2003). The disease specificity of inefficient GluR2 Q/R site editing implies the pathogenic relevance of ADAR2 insufficiency in the death of motor neurons in sporadic ALS but leaves open the possibility that other genes whose products remain unedited by ADAR2 insufficiency might contribute to the demise of motor neurons.…”

Section: Introductionmentioning

confidence: 59%

Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2

Hideyama

Yamashita

Suzuki³

et al. 2010

J. Neurosci.

142

151

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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 2ϩ 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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Section: Introductionmentioning

confidence: 59%

Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2

Hideyama

Yamashita

Suzuki³

et al. 2010

J. Neurosci.

142

151

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“…This generates a lethal phenotype characterized by seizures and acute neurodegeneration (21). GluR2-editing defects also have implications in ALS, because a significant reduction in RNA editing of GluR2 at the Q=R site occurred specifically in motor neurons of five patients with sporadic ALS (74,81). In support of a crucial role for GluR2 in controlling Ca 2þ influx through the AMPA-receptor complex, the evidence indicates that the overexpression of a GluR2-deficient Ca 2þ -permeable AMPA receptor in mice leads to a late-onset motorneuron degenerative disorder, which is exacerbated when coexpressed with the mutant SOD1 transgene (78,79).…”

Section: Glutamate Receptor-mediated Excitotoxicity In Alsmentioning

confidence: 99%

Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

Foran

Trotti²

2009

Antioxidants & Redox Signaling

248

141

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Responsible for the majority of excitatory activity in the central nervous system (CNS), glutamate interacts with a range of specific receptor and transporter systems to establish a functional synapse. Excessive stimulation of glutamate receptors causes excitotoxicity, a phenomenon implicated in both acute and chronic neurodegenerative diseases [e.g., ischemia, Huntington's disease, and amyotrophic lateral sclerosis (ALS)]. In physiology, excitotoxicity is prevented by rapid binding and clearance of synaptic released glutamate by high-affinity, Na þ -dependent glutamate transporters and amplified by defects to the glutamate transporter and receptor systems. ALS pathogenetic mechanisms are not completely understood and characterized, but excitotoxicity has been regarded as one firm mechanism implicated in the disease because of data obtained from ALS patients and animal and cellular models as well as inferred by the documented efficacy of riluzole, a generic antiglutamatergic drug, has in patients. In this article, we critically review the several lines of evidence supporting a role for glutamate-mediated excitotoxicity in the death of motor neurons occurring in ALS, putting a particular emphasis on the impairment of the glutamate-transport system. Antioxid. Redox Signal. 11, 1587-1602. Glutamate in the Central Nervous SystemL -Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS). A nonessential amino acid, glutamate is continuously converted to a-ketoglutarate through deamination by glutamate dehydrogenase or by transamination by one of the transaminases and metabolized through the tricarboxylic acid cycle to succinate, fumarate, and malate, successively. Glutamate is also the product of the deamination of glutamine by phosphateactivated glutaminase, a mitochondrial and possibly neuronspecific enzyme (80). Synaptically released glutamate activates a family of ligand-gated ion channels (ionotropic receptors) and G protein-coupled receptors (metabotropic receptors), and its action is terminated by specific reuptake systems located mainly in astrocytes surrounding the synapse. In astrocytes, glutamate is then converted into glutamine, which does not have neurotransmitter properties and can be released and made available for neurons to convert it back to glutamate through a glutamine-reuptake system. Glutamate is then packed by vesicular glutamate transporters in synaptic vesicles, ready to be released again (35,129) (Fig. 1).

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“…In the diseased neurons editing of the GluR-2 Q/R position was severely decreased in most samples (ranging from 62-100%) whereas all control cells showed 100% editing 55 . The deficiency in RNA editing of the GluR-2 Q/R position is not detected in motor neurons of rats transgenic for mutant human SOD1 (an animal model for families with ALS) or in those of patients with spinal and bulbar muscular atrophy, a non-ALS motor neuron disease 57 . These findings indicate that abnormal editing may be a contributory cause of neuronal death specifically in sporadic ALS 56 .…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

A-to-I RNA Editing and Human Disease

Maas

Kawahara²,

Tamburro³

et al. 2006

RNA Biology

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246

205

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The post-transcriptional modification of mammalian transcripts by A-to-I RNA editing has been recognized as an important mechanism for the generation of molecular diversity and also regulates protein function through recoding of genomic information. As the molecular players of editing are characterized and an increasing number of genes become identified that are subject to A-to-I modification, the potential impact of editing on the etiology or progression of human diseases is realized. Here we review the recent knowledge on where disturbances in A-to-I RNA editing have been correlated with human disease phenotypes.

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Underediting of GluR2 mRNA, a neuronal death inducing molecular change in sporadic ALS, does not occur in motor neurons in ALS1 or SBMA

Cited by 59 publications

References 16 publications

Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2

Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2

Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

A-to-I RNA Editing and Human Disease

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