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  1. Zhihui Yang, Fan Lin, Claudia S Robertson and Kevin K W Wang.
    Dual vulnerability of TDP-43 to calpain and caspase-3 proteolysis after neurotoxic conditions and traumatic brain injury.. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2014.
    Abstract Transactivation response DNA-binding protein 43 (TDP-43) proteinopathy has recently been reported in chronic traumatic encephalopathy, a neurodegenerative condition linked to prior history of traumatic brain injury (TBI). While TDP-43 appears to be vulnerable to proteolytic modifications under neurodegenerative conditions, the mechanism underlying the contribution of TDP-43 to the pathogenesis of TBI remains unknown. In this study, we first mapped out the calpain or caspase-3 TDP-43 fragmentation patterns by in vitro protease digestion. Concurrently, in cultured cerebrocortical neurons subjected to cell death challenges, we identified distinct TDP-43 breakdown products (BDPs) of 35, 33, and 12 kDa that were indicative of dual calpain/caspase attack. Cerebrocortical culture incubated with calpain and caspase-fragmented TDP-43 resulted in neuronal injury. Furthermore, increased TDP-43 BDPs as well as redistributed TDP-43 from the nucleus to the cytoplasm were observed in the mouse cortex in two TBI models: controlled cortical impact injury and overpressure blast-wave-induced brain injury. Finally, TDP-43 and its 35 kDa fragment levels were also elevated in the cerebrospinal fluid (CSF) of severe TBI patients. This is the first evidence that TDP-43 might be involved in acute neuroinjury and TBI pathology, and that TDP-43 and its fragments may have biomarker utilities in TBI patients.Journal of Cerebral Blood Flow & Metabolism advance online publication, 11 June 2014; doi:10.1038/jcbfm.2014.105.
    URL, DOI BibTeX

    @article{Yang2014,
    	abstract = "Transactivation response DNA-binding protein 43 (TDP-43) proteinopathy has recently been reported in chronic traumatic encephalopathy, a neurodegenerative condition linked to prior history of traumatic brain injury (TBI). While TDP-43 appears to be vulnerable to proteolytic modifications under neurodegenerative conditions, the mechanism underlying the contribution of TDP-43 to the pathogenesis of TBI remains unknown. In this study, we first mapped out the calpain or caspase-3 TDP-43 fragmentation patterns by in vitro protease digestion. Concurrently, in cultured cerebrocortical neurons subjected to cell death challenges, we identified distinct TDP-43 breakdown products (BDPs) of 35, 33, and 12 kDa that were indicative of dual calpain/caspase attack. Cerebrocortical culture incubated with calpain and caspase-fragmented TDP-43 resulted in neuronal injury. Furthermore, increased TDP-43 BDPs as well as redistributed TDP-43 from the nucleus to the cytoplasm were observed in the mouse cortex in two TBI models: controlled cortical impact injury and overpressure blast-wave-induced brain injury. Finally, TDP-43 and its 35 kDa fragment levels were also elevated in the cerebrospinal fluid (CSF) of severe TBI patients. This is the first evidence that TDP-43 might be involved in acute neuroinjury and TBI pathology, and that TDP-43 and its fragments may have biomarker utilities in TBI patients.Journal of Cerebral Blood Flow \& Metabolism advance online publication, 11 June 2014; doi:10.1038/jcbfm.2014.105.",
    	author = "Yang, Zhihui and Lin, Fan and Robertson, Claudia S and Wang, Kevin K W",
    	doi = "10.1038/jcbfm.2014.105",
    	issn = "1559-7016",
    	journal = "Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism",
    	month = "",
    	pmid = 24917042,
    	title = "{Dual vulnerability of TDP-43 to calpain and caspase-3 proteolysis after neurotoxic conditions and traumatic brain injury.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24917042",
    	year = 2014
    }
    
  2. Mie Kubota-Sakashita, Kazuya Iwamoto, Miki Bundo and Tadafumi Kato.
    A role of ADAR2 and RNA editing of glutamate receptors in mood disorders and schizophrenia.. Molecular brain 7:5, January 2014.
    Abstract BACKGROUND: Pre-mRNAs of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-propanoic acid (AMPA)/kainate glutamate receptors undergo post-transcriptional modification known as RNA editing that is mediated by adenosine deaminase acting on RNA type 2 (ADAR2). This modification alters the amino acid sequence and function of the receptor. Glutamatergic signaling has been suggested to have a role in mood disorders and schizophrenia, but it is unknown whether altered RNA editing of AMPA/kainate receptors has pathophysiological significance in these mental disorders. In this study, we found that ADAR2 expression tended to be decreased in the postmortem brains of patients with schizophrenia and bipolar disorder. RESULTS: Decreased ADAR2 expression was significantly correlated with decreased editing of the R/G sites of AMPA receptors. In heterozygous Adar2 knockout mice (Adar2+/- mice), editing of the R/G sites of AMPA receptors was decreased. Adar2+/- mice showed a tendency of increased activity in the open-field test and a tendency of resistance to immobility in the forced swimming test. They also showed enhanced amphetamine-induced hyperactivity. There was no significant difference in amphetamine-induced hyperactivity between Adar2+/- and wild type mice after the treatment with an AMPA/kainate receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline. CONCLUSIONS: These findings collectively suggest that altered RNA editing efficiency of AMPA receptors due to down-regulation of ADAR2 has a possible role in the pathophysiology of mental disorders.
    URL, DOI BibTeX

    @article{Kubota-Sakashita2014,
    	abstract = "BACKGROUND: Pre-mRNAs of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-propanoic acid (AMPA)/kainate glutamate receptors undergo post-transcriptional modification known as RNA editing that is mediated by adenosine deaminase acting on RNA type 2 (ADAR2). This modification alters the amino acid sequence and function of the receptor. Glutamatergic signaling has been suggested to have a role in mood disorders and schizophrenia, but it is unknown whether altered RNA editing of AMPA/kainate receptors has pathophysiological significance in these mental disorders. In this study, we found that ADAR2 expression tended to be decreased in the postmortem brains of patients with schizophrenia and bipolar disorder. RESULTS: Decreased ADAR2 expression was significantly correlated with decreased editing of the R/G sites of AMPA receptors. In heterozygous Adar2 knockout mice (Adar2+/- mice), editing of the R/G sites of AMPA receptors was decreased. Adar2+/- mice showed a tendency of increased activity in the open-field test and a tendency of resistance to immobility in the forced swimming test. They also showed enhanced amphetamine-induced hyperactivity. There was no significant difference in amphetamine-induced hyperactivity between Adar2+/- and wild type mice after the treatment with an AMPA/kainate receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline. CONCLUSIONS: These findings collectively suggest that altered RNA editing efficiency of AMPA receptors due to down-regulation of ADAR2 has a possible role in the pathophysiology of mental disorders.",
    	author = "Kubota-Sakashita, Mie and Iwamoto, Kazuya and Bundo, Miki and Kato, Tadafumi",
    	doi = "10.1186/1756-6606-7-5",
    	issn = "1756-6606",
    	journal = "Molecular brain",
    	month = "jan",
    	pages = 5,
    	pmid = 24443933,
    	title = "{A role of ADAR2 and RNA editing of glutamate receptors in mood disorders and schizophrenia.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3902024\&tool=pmcentrez\&rendertype=abstract",
    	volume = 7,
    	year = 2014
    }
    
  3. Takenari Yamashita and Shin Kwak.
    The molecular link between inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in motor neurons of sporadic amyotrophic lateral sclerosis patients.. Brain research, 2013.
    Abstract TAR DNA-binding protein (TDP-43) pathology and reduced expression of adenosine deaminase acting on RNA 2 (ADAR2), which is the RNA editing enzyme responsible for adenosine-to-inosine conversion at the GluA2 glutamine/arginine (Q/R) site, concomitantly occur in the same motor neurons of amyotrophic lateral sclerosis (ALS) patients; this finding suggests a link between these two ALS-specific molecular abnormalities. AMPA receptors containing Q/R site-unedited GluA2 in their subunit assembly are Ca(2+)-permeable, and motor neurons lacking ADAR2 undergo slow death in conditional ADAR2 knockout (AR2) mice, which is a mechanistic ALS model in which the ADAR2 gene is targeted in cholinergic neurons. Moreover, deficient ADAR2 induced mislocalization of TDP-43 similar to TDP-43 pathology seen in the sporadic ALS patients in the motor neurons of AR2 mice. The abnormal mislocalization of TDP-43 specifically resulted from activation of the Ca(2+)-dependent serine protease calpain that specifically cleaved TDP-43 at the C-terminal region, and generated aggregation-prone N-terminal fragments. Notably, the N-terminal fragments of TDP-43 lacking the C-terminus were demonstrated in the brains and spinal cords of ALS patients. Because normalization of either the Ca(2+)-permeability of AMPA receptors or the calpain activity in the motor neurons normalized the subcellular localization of TDP-43 in AR2 mice, it is likely that exaggerated calpain-dependent TDP-43 fragments played a role at least in the initiation of TDP-43 pathology. Elucidation of the molecular cascade of neuronal death induced by ADAR2 downregulation could provide a new specific therapy for sporadic ALS. In this review, we summarized the work from our group on the role of inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in sporadic ALS, and discussed possible effects of inefficient ADAR2-mediated RNA editing in general. This article is part of a Special Issue entitled RNA Metabolism 2013.
    URL, DOI BibTeX

    @article{Yamashita2013,
    	abstract = "TAR DNA-binding protein (TDP-43) pathology and reduced expression of adenosine deaminase acting on RNA 2 (ADAR2), which is the RNA editing enzyme responsible for adenosine-to-inosine conversion at the GluA2 glutamine/arginine (Q/R) site, concomitantly occur in the same motor neurons of amyotrophic lateral sclerosis (ALS) patients; this finding suggests a link between these two ALS-specific molecular abnormalities. AMPA receptors containing Q/R site-unedited GluA2 in their subunit assembly are Ca(2+)-permeable, and motor neurons lacking ADAR2 undergo slow death in conditional ADAR2 knockout (AR2) mice, which is a mechanistic ALS model in which the ADAR2 gene is targeted in cholinergic neurons. Moreover, deficient ADAR2 induced mislocalization of TDP-43 similar to TDP-43 pathology seen in the sporadic ALS patients in the motor neurons of AR2 mice. The abnormal mislocalization of TDP-43 specifically resulted from activation of the Ca(2+)-dependent serine protease calpain that specifically cleaved TDP-43 at the C-terminal region, and generated aggregation-prone N-terminal fragments. Notably, the N-terminal fragments of TDP-43 lacking the C-terminus were demonstrated in the brains and spinal cords of ALS patients. Because normalization of either the Ca(2+)-permeability of AMPA receptors or the calpain activity in the motor neurons normalized the subcellular localization of TDP-43 in AR2 mice, it is likely that exaggerated calpain-dependent TDP-43 fragments played a role at least in the initiation of TDP-43 pathology. Elucidation of the molecular cascade of neuronal death induced by ADAR2 downregulation could provide a new specific therapy for sporadic ALS. In this review, we summarized the work from our group on the role of inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in sporadic ALS, and discussed possible effects of inefficient ADAR2-mediated RNA editing in general. This article is part of a Special Issue entitled RNA Metabolism 2013.",
    	author = "Yamashita, Takenari and Kwak, Shin",
    	doi = "10.1016/j.brainres.2013.12.011",
    	issn = "1872-6240",
    	journal = "Brain research",
    	month = "",
    	pmid = 24355598,
    	title = "{The molecular link between inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in motor neurons of sporadic amyotrophic lateral sclerosis patients.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24355598",
    	year = 2013
    }
    
  4. Takenari Yamashita, Hui Lin Chai, Sayaka Teramoto, Shoji Tsuji, Kuniko Shimazaki, Shin-ichi Muramatsu and Shin Kwak.
    Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons.. EMBO molecular medicine 5(11):1710–9, 2013.
    Abstract Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, and the lack of effective therapy results in inevitable death within a few years of onset. Failure of GluA2 RNA editing resulting from downregulation of the RNA-editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) occurs in the majority of ALS cases and causes the death of motor neurons via a Ca(2+) -permeable AMPA receptor-mediated mechanism. Here, we explored the possibility of gene therapy for ALS by upregulating ADAR2 in mouse motor neurons using an adeno-associated virus serotype 9 (AAV9) vector that provides gene delivery to a wide array of central neurons after peripheral administration. A single intravenous injection of AAV9-ADAR2 in conditional ADAR2 knockout mice (AR2), which comprise a mechanistic mouse model of sporadic ALS, caused expression of exogenous ADAR2 in the central neurons and effectively prevented progressive motor dysfunction. Notably, AAV9-ADAR2 rescued the motor neurons of AR2 mice from death by normalizing TDP-43 expression. This AAV9-mediated ADAR2 gene delivery may therefore enable the development of a gene therapy for ALS.
    URL, DOI BibTeX

    @article{Yamashita2013a,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, and the lack of effective therapy results in inevitable death within a few years of onset. Failure of GluA2 RNA editing resulting from downregulation of the RNA-editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) occurs in the majority of ALS cases and causes the death of motor neurons via a Ca(2+) -permeable AMPA receptor-mediated mechanism. Here, we explored the possibility of gene therapy for ALS by upregulating ADAR2 in mouse motor neurons using an adeno-associated virus serotype 9 (AAV9) vector that provides gene delivery to a wide array of central neurons after peripheral administration. A single intravenous injection of AAV9-ADAR2 in conditional ADAR2 knockout mice (AR2), which comprise a mechanistic mouse model of sporadic ALS, caused expression of exogenous ADAR2 in the central neurons and effectively prevented progressive motor dysfunction. Notably, AAV9-ADAR2 rescued the motor neurons of AR2 mice from death by normalizing TDP-43 expression. This AAV9-mediated ADAR2 gene delivery may therefore enable the development of a gene therapy for ALS.",
    	author = "Yamashita, Takenari and Chai, Hui Lin and Teramoto, Sayaka and Tsuji, Shoji and Shimazaki, Kuniko and Muramatsu, Shin-ichi and Kwak, Shin",
    	doi = "10.1002/emmm.201302935",
    	issn = "1757-4684",
    	journal = "EMBO molecular medicine",
    	keywords = "Adenosine Deaminase,Adenosine Deaminase: genetics,Adenosine Deaminase: metabolism,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: enzymology,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: therapy,Animals,Brain,Brain: cytology,Brain: enzymology,Brain: virology,Dependovirus,Dependovirus: genetics,Dependovirus: physiology,Disease Models, Animal,Genetic Therapy,Genetic Vectors,Genetic Vectors: genetics,Genetic Vectors: physiology,Humans,Mice,Mice, Knockout,Mice, Transgenic,Motor Neurons,Motor Neurons: enzymology,RNA-Binding Proteins,RNA-Binding Proteins: genetics,RNA-Binding Proteins: metabolism",
    	month = "",
    	number = 11,
    	pages = "1710--9",
    	pmid = 24115583,
    	title = "{Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3840487\&tool=pmcentrez\&rendertype=abstract",
    	volume = 5,
    	year = 2013
    }
    
  5. Christopher S Brower, Konstantin I Piatkov and Alexander Varshavsky.
    Neurodegeneration-associated protein fragments as short-lived substrates of the N-end rule pathway.. Molecular cell 50(2):161–71, 2013.
    Abstract Protein aggregates are a common feature of neurodegenerative syndromes. Specific protein fragments were found to be aggregated in disorders including Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Here, we show that the natural C-terminal fragments of Tau, TDP43, and $\alpha$-synuclein are short-lived substrates of the Arg/N-end rule pathway, a processive proteolytic system that targets proteins bearing "destabilizing" N-terminal residues. Furthermore, a natural TDP43 fragment is shown to be metabolically stabilized in Ate1(-/-) fibroblasts that lack the arginylation branch of the Arg/N-end rule pathway, leading to accumulation and aggregation of this fragment. We also found that a fraction of A$\beta$42, the Alzheimer's disease-associated fragment of APP, is N-terminally arginylated in the brains of 5xFAD mice and is degraded by the Arg/N-end rule pathway. The discovery that neurodegeneration-associated natural fragments of TDP43, Tau, $\alpha$-synuclein, and APP can be selectively destroyed by the Arg/N-end rule pathway suggests that this pathway counteracts neurodegeneration.
    URL, DOI BibTeX

    @article{Brower2013,
    	abstract = {Protein aggregates are a common feature of neurodegenerative syndromes. Specific protein fragments were found to be aggregated in disorders including Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Here, we show that the natural C-terminal fragments of Tau, TDP43, and $\alpha$-synuclein are short-lived substrates of the Arg/N-end rule pathway, a processive proteolytic system that targets proteins bearing "destabilizing" N-terminal residues. Furthermore, a natural TDP43 fragment is shown to be metabolically stabilized in Ate1(-/-) fibroblasts that lack the arginylation branch of the Arg/N-end rule pathway, leading to accumulation and aggregation of this fragment. We also found that a fraction of A$\beta$42, the Alzheimer's disease-associated fragment of APP, is N-terminally arginylated in the brains of 5xFAD mice and is degraded by the Arg/N-end rule pathway. The discovery that neurodegeneration-associated natural fragments of TDP43, Tau, $\alpha$-synuclein, and APP can be selectively destroyed by the Arg/N-end rule pathway suggests that this pathway counteracts neurodegeneration.},
    	author = "Brower, Christopher S and Piatkov, Konstantin I and Varshavsky, Alexander",
    	doi = "10.1016/j.molcel.2013.02.009",
    	issn = "1097-4164",
    	journal = "Molecular cell",
    	keywords = "Amino Acid Sequence,Amyloid beta-Protein Precursor,Amyloid beta-Protein Precursor: chemistry,Amyloid beta-Protein Precursor: metabolism,Animals,Arginine,Arginine: metabolism,Brain,Brain: metabolism,Calpain,Calpain: metabolism,Cell Extracts,DNA-Binding Proteins,DNA-Binding Proteins: chemistry,DNA-Binding Proteins: metabolism,Frontotemporal Lobar Degeneration,Frontotemporal Lobar Degeneration: metabolism,HEK293 Cells,Half-Life,Humans,Matrix Metalloproteinase 3,Matrix Metalloproteinase 3: metabolism,Mice,Mice, Transgenic,Molecular Sequence Data,NIH 3T3 Cells,Neurodegenerative Diseases,Neurodegenerative Diseases: metabolism,Peptide Fragments,Peptide Fragments: chemistry,Peptide Fragments: metabolism,Protein Stability,Proteolysis,Reticulocytes,Reticulocytes: metabolism,Saccharomyces cerevisiae,alpha-Synuclein,alpha-Synuclein: chemistry,alpha-Synuclein: metabolism,tau Proteins,tau Proteins: chemistry,tau Proteins: metabolism",
    	month = "",
    	number = 2,
    	pages = "161--71",
    	pmid = 23499006,
    	title = "{Neurodegeneration-associated protein fragments as short-lived substrates of the N-end rule pathway.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3640747\&tool=pmcentrez\&rendertype=abstract",
    	volume = 50,
    	year = 2013
    }
    
  6. Liu Yang, Ping Huang, Feng Li, Liyun Zhao, Yongliang Zhang, Shoufeng Li, Zhenji Gan, Anning Lin, Wenjun Li and Yong Liu.
    c-Jun amino-terminal kinase-1 mediates glucose-responsive upregulation of the RNA editing enzyme ADAR2 in pancreatic beta-cells.. PloS one 7(11):e48611, January 2012.
    Abstract A-to-I RNA editing catalyzed by the two main members of the adenosine deaminase acting on RNA (ADAR) family, ADAR1 and ADAR2, represents a RNA-based recoding mechanism implicated in a variety of cellular processes. Previously we have demonstrated that the expression of ADAR2 in pancreatic islet $\beta$-cells is responsive to the metabolic cues and ADAR2 deficiency affects regulated cellular exocytosis. To investigate the molecular mechanism by which ADAR2 is metabolically regulated, we found that in cultured $\beta$-cells and primary islets, the stress-activated protein kinase JNK1 mediates the upregulation of ADAR2 in response to changes of the nutritional state. In parallel with glucose induction of ADAR2 expression, JNK phosphorylation was concurrently increased in insulin-secreting INS-1 $\beta$-cells. Pharmacological inhibition of JNKs or siRNA knockdown of the expression of JNK1 prominently suppressed glucose-augmented ADAR2 expression, resulting in decreased efficiency of ADAR2 auto-editing. Consistently, the mRNA expression of Adar2 was selectively reduced in the islets from JNK1 null mice in comparison with that of wild-type littermates or JNK2 null mice, and ablation of JNK1 diminished high-fat diet-induced Adar2 expression in the islets from JNK1 null mice. Furthermore, promoter analysis of the mouse Adar2 gene identified a glucose-responsive region and revealed the transcription factor c-Jun as a driver of Adar2 transcription. Taken together, these results demonstrate that JNK1 serves as a crucial component in mediating glucose-responsive upregulation of ADAR2 expression in pancreatic $\beta$-cells. Thus, the JNK1 pathway may be functionally linked to the nutrient-sensing actions of ADAR2-mediated RNA editing in professional secretory cells.
    URL, DOI BibTeX

    @article{Yang2012,
    	abstract = "A-to-I RNA editing catalyzed by the two main members of the adenosine deaminase acting on RNA (ADAR) family, ADAR1 and ADAR2, represents a RNA-based recoding mechanism implicated in a variety of cellular processes. Previously we have demonstrated that the expression of ADAR2 in pancreatic islet $\beta$-cells is responsive to the metabolic cues and ADAR2 deficiency affects regulated cellular exocytosis. To investigate the molecular mechanism by which ADAR2 is metabolically regulated, we found that in cultured $\beta$-cells and primary islets, the stress-activated protein kinase JNK1 mediates the upregulation of ADAR2 in response to changes of the nutritional state. In parallel with glucose induction of ADAR2 expression, JNK phosphorylation was concurrently increased in insulin-secreting INS-1 $\beta$-cells. Pharmacological inhibition of JNKs or siRNA knockdown of the expression of JNK1 prominently suppressed glucose-augmented ADAR2 expression, resulting in decreased efficiency of ADAR2 auto-editing. Consistently, the mRNA expression of Adar2 was selectively reduced in the islets from JNK1 null mice in comparison with that of wild-type littermates or JNK2 null mice, and ablation of JNK1 diminished high-fat diet-induced Adar2 expression in the islets from JNK1 null mice. Furthermore, promoter analysis of the mouse Adar2 gene identified a glucose-responsive region and revealed the transcription factor c-Jun as a driver of Adar2 transcription. Taken together, these results demonstrate that JNK1 serves as a crucial component in mediating glucose-responsive upregulation of ADAR2 expression in pancreatic $\beta$-cells. Thus, the JNK1 pathway may be functionally linked to the nutrient-sensing actions of ADAR2-mediated RNA editing in professional secretory cells.",
    	author = "Yang, Liu and Huang, Ping and Li, Feng and Zhao, Liyun and Zhang, Yongliang and Li, Shoufeng and Gan, Zhenji and Lin, Anning and Li, Wenjun and Liu, Yong",
    	doi = "10.1371/journal.pone.0048611",
    	issn = "1932-6203",
    	journal = "PloS one",
    	keywords = "Adenosine Deaminase,Adenosine Deaminase: genetics,Adenosine Deaminase: metabolism,Animals,Calcium Signaling,Calcium Signaling: drug effects,Diet, High-Fat,Enzyme Activation,Enzyme Activation: drug effects,Female,Gene Knockdown Techniques,Glucose,Glucose: metabolism,Glucose: pharmacology,Insulin-Secreting Cells,Insulin-Secreting Cells: drug effects,Insulin-Secreting Cells: enzymology,Mice,Mice, Knockout,Mitogen-Activated Protein Kinase 8,Mitogen-Activated Protein Kinase 8: metabolism,Obesity,Obesity: enzymology,Obesity: genetics,Obesity: pathology,Phosphorylation,Phosphorylation: drug effects,Promoter Regions, Genetic,Promoter Regions, Genetic: genetics,RNA Editing,RNA Editing: drug effects,RNA Editing: genetics,Rats,Up-Regulation,Up-Regulation: drug effects,Up-Regulation: genetics",
    	month = "jan",
    	number = 11,
    	pages = "e48611",
    	pmid = 23139803,
    	title = "{c-Jun amino-terminal kinase-1 mediates glucose-responsive upregulation of the RNA editing enzyme ADAR2 in pancreatic beta-cells.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3490865\&tool=pmcentrez\&rendertype=abstract",
    	volume = 7,
    	year = 2012
    }
    
  7. Takenari Yamashita, Takuto Hideyama, Kosuke Hachiga, Sayaka Teramoto, Jiro Takano, Nobuhisa Iwata, Takaomi C Saido and Shin Kwak.
    A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology.. Nature communications 3:1307, January 2012.
    Abstract Both mislocalization of TDP-43 and downregulation of RNA-editing enzyme ADAR2 co-localize 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 Ca2+-dependent cysteine protease, by upregulation of Ca2+-permeable AMPA receptors generates carboxy-terminal-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 Ca2+-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.
    URL, DOI BibTeX

    @article{Yamashita2012,
    	abstract = "Both mislocalization of TDP-43 and downregulation of RNA-editing enzyme ADAR2 co-localize 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 Ca2+-dependent cysteine protease, by upregulation of Ca2+-permeable AMPA receptors generates carboxy-terminal-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 Ca2+-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.",
    	author = "Yamashita, Takenari and Hideyama, Takuto and Hachiga, Kosuke and Teramoto, Sayaka and Takano, Jiro and Iwata, Nobuhisa and Saido, Takaomi C and Kwak, Shin",
    	doi = "10.1038/ncomms2303",
    	issn = "2041-1723",
    	journal = "Nature communications",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Blotting, Western,Calpain,Calpain: physiology,DNA-Binding Proteins,DNA-Binding Proteins: metabolism,DNA-Binding Proteins: physiology,HeLa Cells,Humans,Mice,Mice, Knockout,Mice, Mutant Strains,Motor Neurons,Motor Neurons: metabolism,Motor Neurons: pathology,Motor Neurons: physiology,Up-Regulation,Up-Regulation: physiology",
    	month = "jan",
    	pages = 1307,
    	pmid = 23250437,
    	title = "{A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23250437",
    	volume = 3,
    	year = 2012
    }
    
  8. Takuto Hideyama, Takenari Yamashita, Hitoshi Aizawa, Shoji Tsuji, Akiyoshi Kakita, Hitoshi Takahashi and Shin Kwak.
    Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons.. Neurobiology of disease 45(3):1121–8, 2012.
    Abstract Amyotrophic lateral sclerosis (ALS) is the most common adult-onset fatal motor neuron disease. In spinal motor neurons of patients with sporadic ALS, normal RNA editing of GluA2, a subunit of the L-$\alpha$-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, is inefficient. Adenosine deaminase acting on RNA 2 (ADAR2) specifically mediates RNA editing at the glutamine/arginine (Q/R) site of GluA2 and motor neurons expressing Q/R site-unedited GluA2 undergo slow death in conditional ADAR2 knockout mice. Therefore, investigation into whether inefficient ADAR2-mediated GluA2 Q/R site-editing occurs universally in motor neurons of patients with ALS would provide insight into the pathogenesis of ALS. We analyzed the extents of GluA2 Q/R site-editing in an individual laser-captured motor neuron of 29 ALS patients compared with those of normal and disease control subjects. In addition, we analyzed the enzymatic activity of three members of the ADAR family (ADAR1, ADAR2 and ADAR3) in ALS motor neurons expressing unedited GluA2 mRNA and those expressing only edited GluA2 mRNA. Q/R site-unedited GluA2 mRNA was expressed in a significant proportion of motor neurons from all of the ALS cases examined. Conversely, motor neurons of the normal and disease control subjects expressed only edited GluA2 mRNA. ADAR2, but not ADAR1 or ADAR3, was significantly downregulated in all the motor neurons of ALS patients, more extensively in those expressing Q/R site-unedited GluA2 mRNA than those expressing only Q/R site-edited GluA2 mRNA. These results indicate that ADAR2 downregulation is a profound pathological change relevant to death of motor neurons in ALS.
    URL, DOI BibTeX

    @article{Hideyama2012,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is the most common adult-onset fatal motor neuron disease. In spinal motor neurons of patients with sporadic ALS, normal RNA editing of GluA2, a subunit of the L-$\alpha$-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, is inefficient. Adenosine deaminase acting on RNA 2 (ADAR2) specifically mediates RNA editing at the glutamine/arginine (Q/R) site of GluA2 and motor neurons expressing Q/R site-unedited GluA2 undergo slow death in conditional ADAR2 knockout mice. Therefore, investigation into whether inefficient ADAR2-mediated GluA2 Q/R site-editing occurs universally in motor neurons of patients with ALS would provide insight into the pathogenesis of ALS. We analyzed the extents of GluA2 Q/R site-editing in an individual laser-captured motor neuron of 29 ALS patients compared with those of normal and disease control subjects. In addition, we analyzed the enzymatic activity of three members of the ADAR family (ADAR1, ADAR2 and ADAR3) in ALS motor neurons expressing unedited GluA2 mRNA and those expressing only edited GluA2 mRNA. Q/R site-unedited GluA2 mRNA was expressed in a significant proportion of motor neurons from all of the ALS cases examined. Conversely, motor neurons of the normal and disease control subjects expressed only edited GluA2 mRNA. ADAR2, but not ADAR1 or ADAR3, was significantly downregulated in all the motor neurons of ALS patients, more extensively in those expressing Q/R site-unedited GluA2 mRNA than those expressing only Q/R site-edited GluA2 mRNA. These results indicate that ADAR2 downregulation is a profound pathological change relevant to death of motor neurons in ALS.",
    	author = "Hideyama, Takuto and Yamashita, Takenari and Aizawa, Hitoshi and Tsuji, Shoji and Kakita, Akiyoshi and Takahashi, Hitoshi and Kwak, Shin",
    	doi = "10.1016/j.nbd.2011.12.033",
    	issn = "1095-953X",
    	journal = "Neurobiology of disease",
    	keywords = "Adenosine Deaminase,Adenosine Deaminase: genetics,Adenosine Deaminase: metabolism,Adult,Aged,Aged, 80 and over,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: pathology,Analysis of Variance,Animals,Bulbar Palsy, Progressive,Bulbar Palsy, Progressive: pathology,Case-Control Studies,Down-Regulation,Down-Regulation: physiology,Female,Humans,Male,Middle Aged,Motor Neurons,Motor Neurons: enzymology,RNA-Binding Proteins,RNA-Binding Proteins: genetics,RNA-Binding Proteins: metabolism,Receptors, AMPA,Receptors, AMPA: genetics,Receptors, AMPA: metabolism,Spinal Cord,Spinal Cord: pathology,Young Adult",
    	month = "",
    	number = 3,
    	pages = "1121--8",
    	pmid = 22226999,
    	title = "{Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22226999",
    	volume = 45,
    	year = 2012
    }
    
  9. Laszlo Siklos.
    Commentary (two hits with one shot: a possibility of simultaneous targeting motor neuron loss and depression in ALS by upregulating ADAR2).. CNS & neurological disorders drug targets 10(8):863, December 2011.
    URL BibTeX

    @article{Siklos2011,
    	author = "Siklos, Laszlo",
    	issn = "1996-3181",
    	journal = "CNS \& neurological disorders drug targets",
    	month = "dec",
    	number = 8,
    	pages = 863,
    	pmid = 22229319,
    	title = "{Commentary (two hits with one shot: a possibility of simultaneous targeting motor neuron loss and depression in ALS by upregulating ADAR2).}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22229319",
    	volume = 10,
    	year = 2011
    }
    
  10. Baoman Li, Shiquen Zhang, Hongyan Zhang, Leif Hertz and Liang Peng.
    Fluoxetine affects GluK2 editing, glutamate-evoked Ca(2+) influx and extracellular signal-regulated kinase phosphorylation in mouse astrocytes.. Journal of psychiatry & neuroscience : JPN 36(5):322–38, 2011.
    Abstract BACKGROUND: We sought to study the effects of chronic exposure to fluoxetine - a selective serotonin reuptake inhibitor (SSRI) and specific 5-HT(2B) receptor agonist in astrocytes - on the expression of kainate receptors (GluK1-5) in cultured astrocytes and in intact brains in mice and on GluK2 editing by adenosine deaminase acting on RNA (ADAR), as well as the ensuing effects of fluoxetine on glutamate-mediated Ca(2+) influx and extracellular signal-regulated kinase (ERK)(1/2) phosphorylation in astrocytes. METHODS: We performed reverse transcription-polymerase chain reaction (PCR) to assess mRNA expression. We analyzed RNA editing with amplification refractory mutation system PCR and complementary DNA sequencing. Protein expression and ERK phosphorylation were assessed using Western blots. We studied gene silencing with specific small interfering RNAs (siRNA), and we studied intracellular Ca(2+) using fluorometry. RESULTS: All GluK subunits were present in the brain in vivo, and GluK2-5 subunits were present in cultured astrocytes. Fluoxetine upregulated GluK2 and ADAR2. Enhanced GluK2 editing by fluoxetine abolished glutamate-mediated increases in intra cellular Ca(2+) and ERK(1/2) phosphorylation. Enhanced editing of GluK2 was prevented by siRNA against the 5-HT(2B) receptor or ADAR2. LIMITATIONS: Limitations of our study include the use of an in vitro system, but our cultured cells in many respects behave like in vivo astrocytes. CONCLUSION: Fluoxetine alters astrocytic glutamatergic function.
    URL, DOI BibTeX

    @article{Li2011,
    	abstract = "BACKGROUND: We sought to study the effects of chronic exposure to fluoxetine - a selective serotonin reuptake inhibitor (SSRI) and specific 5-HT(2B) receptor agonist in astrocytes - on the expression of kainate receptors (GluK1-5) in cultured astrocytes and in intact brains in mice and on GluK2 editing by adenosine deaminase acting on RNA (ADAR), as well as the ensuing effects of fluoxetine on glutamate-mediated Ca(2+) influx and extracellular signal-regulated kinase (ERK)(1/2) phosphorylation in astrocytes. METHODS: We performed reverse transcription-polymerase chain reaction (PCR) to assess mRNA expression. We analyzed RNA editing with amplification refractory mutation system PCR and complementary DNA sequencing. Protein expression and ERK phosphorylation were assessed using Western blots. We studied gene silencing with specific small interfering RNAs (siRNA), and we studied intracellular Ca(2+) using fluorometry. RESULTS: All GluK subunits were present in the brain in vivo, and GluK2-5 subunits were present in cultured astrocytes. Fluoxetine upregulated GluK2 and ADAR2. Enhanced GluK2 editing by fluoxetine abolished glutamate-mediated increases in intra cellular Ca(2+) and ERK(1/2) phosphorylation. Enhanced editing of GluK2 was prevented by siRNA against the 5-HT(2B) receptor or ADAR2. LIMITATIONS: Limitations of our study include the use of an in vitro system, but our cultured cells in many respects behave like in vivo astrocytes. CONCLUSION: Fluoxetine alters astrocytic glutamatergic function.",
    	author = "Li, Baoman and Zhang, Shiquen and Zhang, Hongyan and Hertz, Leif and Peng, Liang",
    	doi = "10.1503/jpn.100094",
    	issn = "1488-2434",
    	journal = "Journal of psychiatry \& neuroscience : JPN",
    	keywords = "Adenosine Deaminase,Adenosine Deaminase: metabolism,Animals,Animals, Outbred Strains,Brain,Brain: metabolism,Calcium,Calcium: metabolism,Cells, Cultured,Extracellular Signal-Regulated MAP Kinases,Extracellular Signal-Regulated MAP Kinases: metabo,Fluoxetine,Fluoxetine: pharmacology,Gene Silencing,Gene Silencing: drug effects,Glutamic Acid,Glutamic Acid: pharmacology,Male,Mice,Phosphorylation,Phosphorylation: drug effects,RNA Editing,RNA Editing: drug effects,RNA, Small Interfering,RNA, Small Interfering: pharmacology,Receptor, Serotonin, 5-HT2B,Receptor, Serotonin, 5-HT2B: metabolism,Receptors, Kainic Acid,Receptors, Kainic Acid: biosynthesis,Serotonin Uptake Inhibitors,Serotonin Uptake Inhibitors: pharmacology,Signal Transduction,Signal Transduction: drug effects,Up-Regulation",
    	month = "",
    	number = 5,
    	pages = "322--38",
    	pmid = 21320410,
    	title = "{Fluoxetine affects GluK2 editing, glutamate-evoked Ca(2+) influx and extracellular signal-regulated kinase phosphorylation in mouse astrocytes.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3163648\&tool=pmcentrez\&rendertype=abstract",
    	volume = 36,
    	year = 2011
    }
    
  11. Takuto Hideyama and Shin Kwak.
    When Does ALS Start? ADAR2-GluA2 Hypothesis for the Etiology of Sporadic ALS.. Frontiers in molecular neuroscience 4:33, 2011.
    Abstract 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.
    URL, DOI BibTeX

    @article{Hideyama2011,
    	abstract = "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.",
    	author = "Hideyama, Takuto and Kwak, Shin",
    	doi = "10.3389/fnmol.2011.00033",
    	issn = "1662-5099",
    	journal = "Frontiers in molecular neuroscience",
    	month = "",
    	pages = 33,
    	pmid = 22102833,
    	title = "{When Does ALS Start? ADAR2-GluA2 Hypothesis for the Etiology of Sporadic ALS.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3214764\&tool=pmcentrez\&rendertype=abstract",
    	volume = 4,
    	year = 2011
    }
    
  12. Shuchen Lee, Guang Yang, Yue Yong, Ying Liu, Liyun Zhao, Jing Xu, Xiaomin Zhang, Yanjie Wan, Chun Feng, Zhiqin Fan, Yong Liu, Jia Luo and Zun-Ji Ke.
    ADAR2-dependent RNA editing of GluR2 is involved in thiamine deficiency-induced alteration of calcium dynamics.. Molecular neurodegeneration 5:54, January 2010.
    Abstract BACKGROUND: Thiamine (vitamin B1) deficiency (TD) causes mild impairment of oxidative metabolism and region-selective neuronal loss in the central nervous system (CNS). TD in animals has been used to model aging-associated neurodegeneration in the brain. The mechanisms of TD-induced neuron death are complex, and it is likely multiple mechanisms interplay and contribute to the action of TD. In this study, we demonstrated that TD significantly increased intracellular calcium concentrations [Ca2+]i in cultured cortical neurons. RESULTS: TD drastically potentiated AMPA-triggered calcium influx and inhibited pre-mRNA editing of GluR2, a Ca2+-permeable subtype of AMPA receptors. The Ca2+ permeability of GluR2 is regulated by RNA editing at the Q/R site. Edited GluR2 (R) subunits form Ca2+-impermeable channels, whereas unedited GluR2 (Q) channels are permeable to Ca2+ flow. TD inhibited Q/R editing of GluR2 and increased the ratio of unedited GluR2. The Q/R editing of GluR2 is mediated by adenosine deaminase acting on RNA 2 (ADAR2). TD selectively decreased ADAR2 expression and its self-editing ability without affecting ADAR1 in cultured neurons and in the brain tissue. Over-expression of ADAR2 reduced AMPA-mediated rise of [Ca2+]i and protected cortical neurons against TD-induced cytotoxicity, whereas down-regulation of ADAR2 increased AMPA-elicited Ca2+ influx and exacerbated TD-induced death of cortical neurons. CONCLUSIONS: Our findings suggest that TD-induced neuronal damage may be mediated by the modulation of ADAR2-dependent RNA Editing of GluR2.
    URL, DOI BibTeX

    @article{Lee2010,
    	abstract = "BACKGROUND: Thiamine (vitamin B1) deficiency (TD) causes mild impairment of oxidative metabolism and region-selective neuronal loss in the central nervous system (CNS). TD in animals has been used to model aging-associated neurodegeneration in the brain. The mechanisms of TD-induced neuron death are complex, and it is likely multiple mechanisms interplay and contribute to the action of TD. In this study, we demonstrated that TD significantly increased intracellular calcium concentrations [Ca2+]i in cultured cortical neurons. RESULTS: TD drastically potentiated AMPA-triggered calcium influx and inhibited pre-mRNA editing of GluR2, a Ca2+-permeable subtype of AMPA receptors. The Ca2+ permeability of GluR2 is regulated by RNA editing at the Q/R site. Edited GluR2 (R) subunits form Ca2+-impermeable channels, whereas unedited GluR2 (Q) channels are permeable to Ca2+ flow. TD inhibited Q/R editing of GluR2 and increased the ratio of unedited GluR2. The Q/R editing of GluR2 is mediated by adenosine deaminase acting on RNA 2 (ADAR2). TD selectively decreased ADAR2 expression and its self-editing ability without affecting ADAR1 in cultured neurons and in the brain tissue. Over-expression of ADAR2 reduced AMPA-mediated rise of [Ca2+]i and protected cortical neurons against TD-induced cytotoxicity, whereas down-regulation of ADAR2 increased AMPA-elicited Ca2+ influx and exacerbated TD-induced death of cortical neurons. CONCLUSIONS: Our findings suggest that TD-induced neuronal damage may be mediated by the modulation of ADAR2-dependent RNA Editing of GluR2.",
    	author = "Lee, Shuchen and Yang, Guang and Yong, Yue and Liu, Ying and Zhao, Liyun and Xu, Jing and Zhang, Xiaomin and Wan, Yanjie and Feng, Chun and Fan, Zhiqin and Liu, Yong and Luo, Jia and Ke, Zun-Ji",
    	doi = "10.1186/1750-1326-5-54",
    	issn = "1750-1326",
    	journal = "Molecular neurodegeneration",
    	month = "jan",
    	pages = 54,
    	pmid = 21110885,
    	title = "{ADAR2-dependent RNA editing of GluR2 is involved in thiamine deficiency-induced alteration of calcium dynamics.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3006372\&tool=pmcentrez\&rendertype=abstract",
    	volume = 5,
    	year = 2010
    }
    
  13. Jun Sawada, Takenari Yamashita, Hitoshi Aizawa, Yoko Aburakawa, Naoyuki Hasebe and Shin Kwak.
    Effects of antidepressants on GluR2 Q/R site-RNA editing in modified HeLa cell line.. Neuroscience research 64(3):251–8, 2009.
    Abstract 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.
    URL, DOI BibTeX

    @article{Sawada2009,
    	abstract = "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.",
    	author = "Sawada, Jun and Yamashita, Takenari and Aizawa, Hitoshi and Aburakawa, Yoko and Hasebe, Naoyuki and Kwak, Shin",
    	doi = "10.1016/j.neures.2009.03.009",
    	issn = "1872-8111",
    	journal = "Neuroscience research",
    	keywords = "Adenosine Deaminase,Adenosine Deaminase: biosynthesis,Adenosine Deaminase: genetics,Amitriptyline,Amitriptyline: administration \& dosage,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: drug therapy,Amyotrophic Lateral Sclerosis: metabolism,Antidepressive Agents,Antidepressive Agents: administration \& dosage,Arginine,Arginine: metabolism,Cyclopropanes,Cyclopropanes: administration \& dosage,Desipramine,Desipramine: administration \& dosage,Fluoxetine,Fluoxetine: administration \& dosage,Fluvoxamine,Fluvoxamine: administration \& dosage,Glutamine,Glutamine: metabolism,HeLa Cells,Humans,Imipramine,Imipramine: administration \& dosage,Morpholines,Morpholines: administration \& dosage,Paroxetine,Paroxetine: administration \& dosage,RNA Editing,RNA Editing: drug effects,RNA, Messenger,RNA, Messenger: genetics,RNA, Messenger: metabolism,Receptors, AMPA,Receptors, AMPA: genetics,Receptors, AMPA: metabolism",
    	month = "",
    	number = 3,
    	pages = "251--8",
    	pmid = 19447293,
    	title = "{Effects of antidepressants on GluR2 Q/R site-RNA editing in modified HeLa cell line.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/19447293",
    	volume = 64,
    	year = 2009
    }