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Genes 2017, 8(2), 60; doi:10.3390/genes8020060

Altered Intracellular Milieu of ADAR2-Deficient Motor Neurons in Amyotrophic Lateral Sclerosis

1
Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
2
Clinical Research Center for Medicine, International University of Health and Welfare, Ichikawa, Chiba 272-0827, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: H. Ulrich Göringer
Received: 17 November 2016 / Revised: 25 January 2017 / Accepted: 26 January 2017 / Published: 8 February 2017
(This article belongs to the Special Issue RNA Editing)
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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. View Full-Text
Keywords: amyotrophic lateral sclerosis (ALS); adenosine deaminase acting on RNA 2 (ADAR2); RNA editing; transactive response DNA-binding protein (TDP-43); Ca2+-permeability amyotrophic lateral sclerosis (ALS); adenosine deaminase acting on RNA 2 (ADAR2); RNA editing; transactive response DNA-binding protein (TDP-43); Ca2+-permeability
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Yamashita, T.; Akamatsu, M.; Kwak, S. Altered Intracellular Milieu of ADAR2-Deficient Motor Neurons in Amyotrophic Lateral Sclerosis. Genes 2017, 8, 60.

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