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Hypothesis & Theory ARTICLE

Front. Mol. Neurosci., 02 November 2011 | http://dx.doi.org/10.3389/fnmol.2011.00033

When does ALS start? ADAR2–GluA2 hypothesis for the etiology of sporadic ALS

Takuto Hideyama1,2 and Shin Kwak1,2*
  • 1 Core Research for Evolutional Science and Technology, Japan Science Technology Agency, Kawaguchi-shi, Saitama, Japan
  • 2 Department of Neurology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. More than 90% of ALS cases are sporadic, and the majority of sporadic ALS patients do not carry mutations in genes causative of familial ALS; therefore, investigation specifically targeting sporadic ALS is needed to discover the pathogenesis. The motor neurons of sporadic ALS patients express unedited GluA2 mRNA at the Q/R site in a disease-specific and motor neuron-selective manner. GluA2 is a subunit of the AMPA receptor, and it has a regulatory role in the Ca2+-permeability of the AMPA receptor after the genomic Q codon is replaced with the R codon in mRNA by adenosine–inosine conversion, which is mediated by adenosine deaminase acting on RNA 2 (ADAR2). Therefore, ADAR2 activity may not be sufficient to edit all GluA2 mRNA expressed in the motor neurons of ALS patients. To investigate whether deficient ADAR2 activity plays pathogenic roles in sporadic ALS, we generated genetically modified mice (AR2) in which the ADAR2 gene was conditionally knocked out in the motor neurons. AR2 mice showed an ALS-like phenotype with the death of ADAR2-lacking motor neurons. Notably, the motor neurons deficient in ADAR2 survived when they expressed only edited GluA2 in AR2/GluR-BR/R (AR2res) mice, in which the endogenous GluA2 alleles were replaced by the GluR-BR allele that encoded edited GluA2. In heterozygous AR2 mice with only one ADAR2 allele, approximately 20% of the spinal motor neurons expressed unedited GluA2 and underwent degeneration, indicating that half-normal ADAR2 activity is not sufficient to edit all GluA2 expressed in motor neurons. It is likely therefore that the expression of unedited GluA2 causes the death of motor neurons in sporadic ALS. We hypothesize that a progressive downregulation of ADAR2 activity plays a critical role in the pathogenesis of sporadic ALS and that the pathological process commences when motor neurons express unedited GluA2.

Keywords: ADAR2, RNA editing, GluA2, Q/R site, ALS, neuronal death, AMPA

Citation: Hideyama T and Kwak S (2011) When does ALS start? ADAR2–GluA2 hypothesis for the etiology of sporadic ALS. Front. Mol. Neurosci. 4:33. doi: 10.3389/fnmol.2011.00033

Received: 02 September 2011; Paper pending published: 29 September 2011;
Accepted: 03 October 2011; Published online: 02 November 2011.

Edited by:

William Wisden, Imperial College, UK

Reviewed by:

Peter H. Seeburg, Max Planck Institute for Medical Research, Germany
William Wisden, Imperial College, UK

Copyright: © 2011 Hideyama and Kwak. This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.

*Correspondence: Shin Kwak, Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. e-mail: kwak-tky@umin.ac.jp