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.
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.
authors.affiliation: CREST, Japan Science and Technology Agency, Japan; Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takenari
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: CREST, Japan Science and Technology Agency, Japan; Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Clinical Research Center for Medicine, International University of Health and Welfare, Ichikawa, Chiba, 272-0827 Japan. Electronic address: kwak-tky@umin.ac.jp.
authors.forename: Shin
authors.initials: S
authors.lastname: Kwak
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002154:Calpain / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000201:enzymology / Q000378:metabolism*; D017393:RNA Editing; D016601:RNA-Binding Proteins / Q000235:genetics; D018091:Receptors, AMPA / Q000235:genetics*; D013116:Spinal Cord / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA; D002154:Calpain; C000595151:ADAR2 protein, mouse; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; C104722:glutamate receptor ionotropic, AMPA 2
keywords: AMPA receptor; Adenosine deaminase acting on RNA 2 (ADAR2); Amyotrophic lateral sclerosis (ALS); Calpain; GluA2; RNA editing; TAR DNA binding protein of 43kDa (TDP-43)