RNA editing and death of motor neurons

Kawahara, Yukio; Ito, Kyoko; Sun, Hui; Aizawa, Hitoshi; Kanazawa, Ichiro; Kwak, Shin

doi:10.1038/427801a

Cited by 494 publications

(363 citation statements)

References 10 publications

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“…The allosteric modulator CTZ strongly attenuates desensitization in flip variants of AMPA receptors, enhancing agonist-induced steady-state current changes. 2 Therefore, the use of CTZ allowed us to study AMPA receptor-mediated toxicity in experimental conditions more similar to those observed in several pathological conditions, such as in global ischemia and in ALS, where the molecular structure of AMPA receptors is changed, 8,9,11,23 leading to an increased Ca 2 þ permeability 7 or a slower desensitization kinetic. 24 In the presence of 100 mM CTZ, glutamate toxicity was concentration-dependent and sensitive to 50 mM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), indicating that toxicity was mediated through GluR4-homomeric AMPA receptors (Figure 1a and b).…”

Section: Resultsmentioning

confidence: 99%

“…10,11 However, the molecular mechanisms of excitotoxicity associated with Ca 2 þ -permeable AMPA receptors are not completely understood. In this work, we investigated the contribution of the GluR4 subunit of AMPA receptors to the excitotoxic response.…”

Section: Discussionmentioning

confidence: 99%

“…7 Recently, Ca 2 þ -permeable AMPA receptors were shown to be crucial for the selective excitotoxic death of CA1 pyramidal neurons observed after transient global ischemia, 8,9 and for the selective neuronal death of spinal motor neurons in amyotrophic lateral sclerosis (ALS). 10,11 Also, in the cholinergic neurons of the basal forebrain, which may be affected in Alzheimer's disease, the Ca 2 þ influx through AMPA/KA receptors was shown to be a factor of preferential vulnerability to KA excitotoxicity when compared with most cortical or basal forebrain neurons. 12 It is interesting to notice that in several systems where Ca 2 þ -permeable AMPA receptors are involved in cell death, 3,10,12 AMPA receptors are particularly enriched in the GluR4 subunit.…”

Section: Introductionmentioning

confidence: 99%

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Excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors involves the AP-1 transcription factor

et al. 2005

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Cells preferentially expressing GluR4-containing a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors are particularly sensitive to excitotoxicity mediated through non-N-methyl-D-aspartate receptors. However, the excitotoxic signalling pathways associated with GluR4-containing AMPA receptors are not known. In this work, we investigated the downstream signals coupled to excitotoxicity mediated by Ca 2+ -permeable GluR4-containing AMPA receptors, using a HEK 293 cell line constitutively expressing the GluR4 flip subunit of AMPA receptors (HEK-GluR4). Glutamate stimulation of GluR4-containing AMPA receptors decreased cell viability, in a calcium-dependent manner, when the receptor desensitisation was prevented with cyclothiazide. The excitotoxic stimulation mediated through GluR4-containing AMPA receptors increased activator protein-1 (AP-1) DNA-binding activity. Inhibition of the AP-1 activity by overexpression of a c-Jun dominant-negative form protected HEK-GluR4 cells against excitotoxic damage. Taken together, the results indicate that overactivation of Ca 2+ -permeable GluR4-containing AMPA receptors is coupled to a death pathway mediated, at least in part, by the AP-1 transcription factor.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors involves the AP-1 transcription factor

et al. 2005

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“…Under-editing of the Q/R site of GluR2 pre-mRNA (FIG. 3a) has been proposed to be responsible for the death of sporadic amyotrophic lateral sclerosis (ALS) motor neurons 66 , as well as apoptotic death of ischaemic neurons during ischaemia caused by cardiac arrest and disruption of the blood flow to the brain 43 . Last, RNA editing of 5-HT 2C R might have some causative relevance to neuropsychiatric disorders, such as depression, as the editing pattern of 5-HT 2C R mRNA (FIG.…”

Section: Rna-editing Deficienciesmentioning

confidence: 99%

Editor meets silencer: crosstalk between RNA editing and RNA interference

Nishikura

2006

Nat Rev Mol Cell Biol

258

263

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The most prevalent type of RNA editing is mediated by ADAR (adenosine deaminase acting on RNA) enzymes, which convert adenosines to inosines (a process known as A→I RNA editing) in double-stranded (ds)RNA substrates. A→I RNA editing was long thought to affect only selected transcripts by altering the proteins they encode. However, genome-wide screening has revealed numerous editing sites within inverted Alu repeats in introns and untranslated regions. Also, recent evidence indicates that A→I RNA editing crosstalks with RNA-interference pathways, which, like A→I RNA editing, involve dsRNAs. A→I RNA editing therefore seems to have additional functions, including the regulation of retrotransposons and gene silencing, which adds a new urgency to the challenges of fully understanding ADAR functions.An RNA transcript is subjected to various maturation processes, such as 5′ capping, splicing, 3′ processing and polyadenylation, after it is transcribed from the gene. Post-transcriptional processing of primary transcripts is essential to generate mature messenger RNAs that are ready to be translated into proteins 1 . RNA editing is a post-transcriptional-processing mechanism that results in an RNA sequence that is different from the one encoded by the genome, and thereby contributes to the diversity of gene products. There are different types of RNA-editing mechanism that either add or delete nucleotides, or that change one nucleotide into another 2 (BOX 1).The type of RNA editing that is most prevalent in higher eukaryotes converts adenosine (A) residues into inosine (I) in double-stranded (ds)RNAs through the action of ADAR (adenosine deaminase acting on RNA) enzymes [3][4][5] . A→I RNA editing of a short dsRNA that has formed between a coding exon and nearby intron sequences can lead to a codon change and an alteration in the protein function. However, it was recently discovered that the most frequent targets of A→I RNA editing seem to be long, but partially double-stranded, RNAs that are formed from inverted Alu repeats and long interspersed element (LINE) repeats located in introns and untranslated regions (UTRs) of mRNAs [6][7][8][9] . Global editing of non-coding RNA might control the expression of genes that harbour these repeat sequences of retrotransposon origin.Post-transcriptional gene regulation can also occur through RNA interference (RNAi), an evolutionarily conserved phenomenon that involves dsRNA molecules 10,11 . Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are non-coding RNAs that are generated by a class of RNase III ribonucleases (specifically, Dicer and Drosha). These small RNAs are incorporated into the RNA-induced silencing complex (RISC), which mediates the RNAi process [12][13][14][15][16] . The idea that the RNAi and A→I RNA editing pathways might compete for a Competing interests statement: The author declares no competing financial interests. [23][24][25] . NIH Public AccessIn this review, I discuss recent findings on new functions of A→I RNA editing in the regulation of non...

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“…Molecular abnormalities specifically occurring in motor neurons of patients with sporadic ALS other than TDP-43 pathology include the expression of glutamine/arginine (Q/R) site-unedited GluA2, a subunit of a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors 11,12 . This molecular abnormality specifically results from reduced levels of an RNA-editing enzyme called adenosine deaminase acting on RNA 2 (ADAR2) among other members of the ADAR family 13,14 .…”

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confidence: 99%

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

et al. 2012

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Both mislocalization of TDP-43 and downregulation of RNA-editing enzyme ADAR2 colocalize in the motor neurons of amyotrophic lateral sclerosis patients, but how they are linked is not clear. Here we demonstrate that activation of calpain, a Ca 2 þ -dependent cysteine protease, by upregulation of Ca 2 þ -permeable AMPA receptors generates carboxyterminal-cleaved TDP-43 fragments and causes mislocalization of TDP-43 in the motor neurons expressing glutamine/arginine site-unedited GluA2 of conditional ADAR2 knockout (AR2) mice that mimic the amyotrophic lateral sclerosis pathology. These abnormalities are inhibited in the AR2res mice that express Ca 2 þ -impermeable AMPA receptors in the absence of ADAR2 and in the calpastatin transgenic mice, but are exaggerated in the calpastatin knockout mice. Additional demonstration of calpain-dependent TDP43 fragments in the spinal cord and brain of amyotrophic lateral sclerosis patients, and high vulnerability of amyotrophic lateral sclerosis-linked mutant TDP43 to cleavage by calpain support the crucial role of the calpain-dependent cleavage of TDP43 in the amyotrophic lateral sclerosis pathology.

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RNA editing and death of motor neurons

Cited by 494 publications

References 10 publications

Excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors involves the AP-1 transcription factor

Excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors involves the AP-1 transcription factor

Editor meets silencer: crosstalk between RNA editing and RNA interference

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

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