title: Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2.
abstract: 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(2+) 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.
authors.affiliation: Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Takuto
authors.initials: T
authors.lastname: Hideyama
authors.forename: Takenari
authors.initials: T
authors.lastname: Yamashita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.forename: Miyoko
authors.initials: M
authors.lastname: Higuchi
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeburg
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Hidemi
authors.initials: H
authors.lastname: Misawa
authors.forename: Shin
authors.initials: S
authors.lastname: Kwak
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency*; D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal; D001933:Brain Stem / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D004576:Electromyography / Q000379:methods; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D006948:Hyperkinesis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000502:physiology*; D018482:Muscle, Skeletal / Q000503:physiopathology; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism; D017393:RNA Editing / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D011930:Reaction Time / Q000235:genetics / Q000502:physiology; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D045442:Rotarod Performance Test / Q000379:methods; D013116:Spinal Cord / Q000166:cytology; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; C077112:Lox protein, mouse; D008249:Protein-Lysine 6-Oxidase; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium
references.citation: N Engl J Med. 1992 May 28;326(22):1464-8
references.pmid: 1349424
references.citation: Science. 1995 Dec 8;270(5242):1677-80
references.pmid: 7502080
references.citation: Neuron. 2006 Mar 2;49(5):719-33
references.pmid: 16504947
references.citation: Mol Neurobiol. 2008 Aug;38(1):78-100
references.pmid: 18686046
references.citation: Nature. 2004 Feb 26;427(6977):801
references.pmid: 14985749
references.citation: Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R233-42
references.pmid: 17911166
references.citation: J Neurosci. 1996 Jul 1;16(13):4069-79
references.pmid: 8753869
references.citation: Amyotroph Lateral Scler. 2009 Feb;10(1):1-14
references.pmid: 19110986
references.citation: Nat Neurosci. 1999 Jan;2(1):57-64
references.pmid: 10195181
references.citation: J Neuropathol Exp Neurol. 2005 Jul;64(7):605-12
references.pmid: 16042312
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14018-23
references.pmid: 14612560
references.citation: Trends Mol Med. 2009 Mar;15(3):89-100
references.pmid: 19230774
references.citation: Cell. 1991 Oct 4;67(1):11-9
references.pmid: 1717158
references.citation: Neuron. 2002 May 30;34(5):759-72
references.pmid: 12062022
references.citation: Eur J Neurosci. 2003 Jul;18(1):23-33
references.pmid: 12859334
references.citation: Neurosci Res. 2008 Jun;61(2):201-6
references.pmid: 18407364
references.citation: Nature. 1996 Feb 1;379(6564):460-4
references.pmid: 8559253
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5826-31
references.pmid: 15827116
references.citation: Nat Biotechnol. 2004 Aug;22(8):1001-5
references.pmid: 15258596
references.citation: J Biol Chem. 2006 Jul 21;281(29):20427-39
references.pmid: 16684769
references.citation: Neuron. 2007 Jun 7;54(5):755-70
references.pmid: 17553424
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13777-82
references.pmid: 9811877
references.citation: Neuron. 1992 Jan;8(1):189-98
references.pmid: 1370372
references.citation: Neurosci Res. 2006 Jan;54(1):11-4
references.pmid: 16225946
references.citation: Science. 2009 May 29;324(5931):1210-3
references.pmid: 19478186
references.citation: Mol Cell Biol. 2006 Jan;26(2):480-8
references.pmid: 16382140
references.citation: Nature. 2000 Jul 6;406(6791):78-81
references.pmid: 10894545
references.citation: J Mol Med (Berl). 2005 Feb;83(2):110-20
references.pmid: 15624111
references.citation: Genesis. 2003 Sep;37(1):44-50
references.pmid: 14502577
references.citation: J Neurochem. 1994 Nov;63(5):1596-602
references.pmid: 7523595
references.citation: Brain Res. 1995 Nov 20;699(2):297-304
references.pmid: 8616634
references.citation: J Neurochem. 2003 May;85(3):680-9
references.pmid: 12694394
references.citation: Neuron. 2003 Nov 13;40(4):763-74
references.pmid: 14622580
references.citation: Neuron. 2002 Jul 3;35(1):17-20
references.pmid: 12123604
references.citation: Nihon Yakurigaku Zasshi. 2003 Dec;122(6):515-26
references.pmid: 14639006
references.citation: Neuropathol Appl Neurobiol. 1993 Aug;19(4):291-9
references.pmid: 8232749
references.citation: Exp Neurol. 2002 Apr;174(2):150-61
references.pmid: 11922657
references.citation: Amyotroph Lateral Scler Other Motor Neuron Disord. 2005 Sep;6(3):131-44
references.pmid: 16183555
references.citation: Nature. 1995 Mar 2;374(6517):77-81
references.pmid: 7870177
references.citation: Ann Neurol. 1999 Dec;46(6):806-15
references.pmid: 10589532