title: Altered Intracellular Milieu of ADAR2-Deficient Motor Neurons in Amyotrophic Lateral Sclerosis.
abstract: Transactive response DNA-binding protein (TDP-43) pathology, and failure of A-to-I conversion (RNA editing) at the glutamine/arginine (Q/R) site of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of most patients with amyotrophic lateral sclerosis (ALS). Adenosine deaminase acting on RNA 2 (ADAR2) specifically catalyzes GluA2 Q/R site-RNA editing. Furthermore, conditional ADAR2 knockout mice (AR2) exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons, which is the most reliable pathological marker of ALS. Therefore, the evidence indicates that ADAR2 downregulation is a causative factor in ALS, and AR2 mice exhibit causative molecular changes that occur in ALS. We discuss the contributors to ADAR2 downregulation and TDP-43 pathology in AR2 mouse motor neurons. We describe mechanisms of exaggerated Ca2+influx amelioration via AMPA receptors, which is neuroprotective in ADAR2-deficient motor neurons with normalization of TDP-43 pathology in AR2 mice. Development of drugs to treat diseases requires appropriate animal models and a sensitive method of evaluating efficacy. Therefore, normalization of disrupted intracellular environments resulting from ADAR2 downregulation may be a therapeutic target for ALS. We discuss the development of targeted therapy for ALS using the AR2 mouse model.
authors.affiliation: Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. yamashitat-tky@umin.net.
authors.forename: Takenari
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. makamatsu@m.u-tokyo.ac.jp.
authors.forename: Megumi
authors.initials: M
authors.lastname: Akamatsu
authors.affiliation: Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. kwak-tky@umin.ac.jp.|Clinical Research Center for Medicine, International University of Health and Welfare, Ichikawa, Chiba 272-0827, Japan. kwak-tky@umin.ac.jp.
authors.forename: Shin
authors.initials: S
authors.lastname: Kwak
keywords: Ca2+-permeability; RNA editing; adenosine deaminase acting on RNA 2 (ADAR2); amyotrophic lateral sclerosis (ALS); transactive response DNA-binding protein (TDP-43)