Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons

Hideyama, Takuto; Yamashita, Takenari; Aizawa, Hitoshi; Tsuji, Shoji; Kakita, Akiyoshi; Takahashi, Hitoshi; Kwak, Shin

doi:10.1016/j.nbd.2011.12.033

Cited by 160 publications

(133 citation statements)

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“…These results suggest that an increase in Ca 2 þ influx through the upregulation of Ca 2 þ -permeable AMPA receptors containing Q/R site-unedited GluA2 activates calpain and that the exaggerated calpain-dependent cleavage of TDP-43 has a crucial role in TDP-43 pathology in ALS motor neurons. The findings that ADAR2 activity is already reduced in ALS motor neurons before they express unedited GluA2 or exhibit TDP-43 pathology 14 and that ADAR2 activity does not change after the overexpression or knockdown of TDP-43 or the expression of TDP-43 fragments or mutant TDP-43 in cultured cells 19 lend further support to our conclusion that the downregulation of ADAR2 is likely an upstream event in the molecular mechanism of TDP-43 pathology in ALS motor neurons 13 . We observed the disappearance of TDP-43 in AR2 mice in the early postnatal weeks but observed cytoplasmic mislocalization of TDP-43 concurrent with the formation of aggregates in the motor neurons of heterozygous AR2H mice (Fig.…”

Section: Discussionsupporting

confidence: 61%

“…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 . ADAR2 specifically catalyses adenosine (A) to inosine (I; A-to-I) conversion 15 at the Q/R site of GluA2 pre-mRNA 16 , thereby making AMPA receptors impermeable to Ca 2 þ (ref.…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 61%

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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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“…More specifically, the glutamate receptor 2 (GluA2) mRNA, which is constitutively edited in some of its nucleotides, has been found to be unedited in motor neurons in individuals with sporadic ALS (Hideyama and Kwak 2011). On the other hand, ADAR2 expression levels were found to be down-regulated in ALS individuals, further supporting the importance of editing in proper motor neuronal functioning (Hideyama et al 2012). In addition, ADAR2 knockout mice show increased cell death rates in their motor neurons (Sasaki et al 2015), in agreement with the results observed in ALS individuals, indicating a pivotal role of A-to-I editing in proper neuronal functioning and brain development in mammals.…”

Section: Neurological Diseasesmentioning

confidence: 99%

“…ALKBH5, also responsible for m 6 A demethylation, has been linked to major depressive disorders (Du et al 2015), suggesting that m 6 A may be playing an important regulatory role in the function of the mammalian brain. A-to-I editing defects have also been associated with neurological diseases (Hideyama and Kwak 2011;Hideyama et al 2012;Gaisler-Salomon et al 2014;Tomaselli et al 2015), such as amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease (Hideyama and Kwak 2011;Hideyama et al 2012). More specifically, the glutamate receptor 2 (GluA2) mRNA, which is constitutively edited in some of its nucleotides, has been found to be unedited in motor neurons in individuals with sporadic ALS (Hideyama and Kwak 2011).…”

Section: Neurological Diseasesmentioning

confidence: 99%

The RNA modification landscape in human disease

Jonkhout

Tran

Smith

et al. 2017

RNA

470

420

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RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases. With the advent of direct RNA-sequencing technologies, we expect that this catalog will help prioritize those RNA modifications for transcriptome-wide maps.

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“…It is well established that RNA editing levels at specific editing sites can change acutely within an organism's lifetime. For example, changes in editing frequency for the mammalian GluA2 and 5-HT 2C receptors have been associated with disease (Gurevich et al, 2002;Hideyama et al, 2011Hideyama et al, , 2010Kawahara et al, 2004;Niswender et al, 2001;Yang et al, 2004). Perhaps a better example comes from Drosophila ADAR itself.…”

Section: Cephalopod Rna Editing Breaks the Rulesmentioning

confidence: 99%

The emerging role of RNA editing in plasticity

Rosenthal¹

2015

Journal of Experimental Biology

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All true metazoans modify their RNAs by converting specific adenosine residues to inosine. Because inosine binds to cytosine, it is a biological mimic for guanosine. This subtle change, termed RNA editing, can have diverse effects on various RNA-mediated cellular pathways, including RNA interference, innate immunity, retrotransposon defense and messenger RNA recoding. Because RNA editing can be regulated, it is an ideal tool for increasing genetic diversity, adaptation and environmental acclimation. This review will cover the following themes related to RNA editing: (1) how it is used to modify different cellular RNAs, (2) how frequently it is used by different organisms to recode mRNA, (3) how specific recoding events regulate protein function, (4) how it is used in adaptation and (5) emerging evidence that it can be used for acclimation. Organismal biologists with an interest in adaptation and acclimation, but with little knowledge of RNA editing, are the intended audience.

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Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons

Cited by 160 publications

References 43 publications

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

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

The RNA modification landscape in human disease

The emerging role of RNA editing in plasticity

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