Human spinal motoneurons express low relative abundance of GluR2 mRNA: an implication for excitotoxicity in ALS

Kawahara, Yukio; Kwak, Shin; Sun, Hui; Ito, Kyoko; Hashida, Hideji; Aizawa, Hitoshi; Jeong, Seon-Yong; Kanazawa, Ichiro

doi:10.1046/j.1471-4159.2003.01703.x

Cited by 110 publications

(67 citation statements)

References 50 publications

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“…However, AMPA receptors missing the GluR2 subunit have been shown to be Ca 2þ permeable (70,152). GluR2-deficient AMPA receptors are expressed in the motor neurons and are implicated in excitotoxic degeneration (34,73,145).…”

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confidence: 99%

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

Foran

Trotti²

2009

Antioxidants & Redox Signaling

241

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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confidence: 99%

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

Foran

Trotti²

2009

Antioxidants & Redox Signaling

241

141

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“…5,6 Considerable data supported the contributions of glutamate-mediated excitotoxicity in ALS. [7][8][9] Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in spinal motoneurons were altered in human ALS 10,11 and G93A-SOD1 mice. [12][13][14] Electrophysiological studies of ALS patients indicated widespread signs of motoneuron hyperexcitability.…”

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Glycinergic Innervation of Motoneurons Is Deficient in Amyotrophic Lateral Sclerosis Mice

Chang

Martin

2009

The American Journal of Pathology

108

138

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Altered motoneuron excitability is involved in amyotrophic lateral sclerosis pathobiology. To test the hypothesis that inhibitory interneuron innervation of spinal motoneurons is abnormal in an amyotrophic lateral sclerosis mouse model, we measured GABAergic, glycinergic, and cholinergic immunoreactive terminals on spinal motoneurons in mice expressing a mutant form of human superoxide dismutase-1 with a Gly933 Ala substitution (G93A-SOD1) and in controls at different ages. Glutamic acid decarboxylase, glycine transporter-2, and choline acetyltransferase were used as markers for GABAergic, glycinergic, and cholinergic terminals, respectively. Triple immunofluorescent labeling of boutons contacting motoneurons was visualized by confocal microscopy and analyzed quantitatively. Glycine transporter-2-bouton density on lateral motoneurons was decreased significantly in G93A-SOD1 mice compared with controls. This reduction was absent at 6 weeks of age but present in asymptomatic 8-week-old mice and worsened with disease progression from 12 to 14 weeks of age. Motoneurons lost most glycinergic innervation by 16 weeks of age (end-stage) when there was a significant decrease in the numbers of motoneurons and choline acetyltransferase-positive boutons. No significant differences in glutamic acid decarboxylase-bouton densities were found in G93A-SOD1 mice. Reduction of glycinergic innervation preceded mitochondrial swelling and vacuolization. Calbindin-positive Renshaw cell number was decreased significantly at 12 weeks of age in G93A-SOD1 mice. Thus, either the selective loss of inhibitory glycinergic regulation of motoneuron function or glycinergic interneuron degeneration contributes to motoneuron degeneration in amyotrophic lateral sclerosis. (Am J

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“…A-I editing has been shown to affect a wide variety of RNA transcripts, both protein coding and noncoding sequences. Its relationship with some neurological diseases, e.g., amyotrophic lateral sclerosis [50,[65][66][67], epilepsy [68], depression [69] and schizophrenia [70], has been clarified. In the skin, although the expression of ADAR1 is recognized, its function remains unknown.…”

Section: Resultsmentioning

confidence: 99%

Dyschromatosis Symmetrica Hereditaria and RNA Editing Enzyme

Kono¹,

Akiyama²

2013

Current Genetics in Dermatology

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Human spinal motoneurons express low relative abundance of GluR2 mRNA: an implication for excitotoxicity in ALS

Cited by 110 publications

References 50 publications

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

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

Glycinergic Innervation of Motoneurons Is Deficient in Amyotrophic Lateral Sclerosis Mice

Dyschromatosis Symmetrica Hereditaria and RNA Editing Enzyme

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