Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2.
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.
Hideyama
Takuto
T
Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Yamashita
Takenari
T
Suzuki
Takeshi
T
Tsuji
Shoji
S
Higuchi
Miyoko
M
Seeburg
Peter H
PH
Takahashi
Ryosuke
R
Misawa
Hidemi
H
Kwak
Shin
S
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
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
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