Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2

Takuto Hideyama, Takenari Yamashita, Takeshi Suzuki, Shoji Tsuji, Miyoko Higuchi, Peter H. Seeburg, Ryosuke Takahashi, Hidemi Misawa, Shin Kwak

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)11917-11925
Number of pages9
JournalJournal of Neuroscience
Volume30
Issue number36
DOIs
Publication statusPublished - 2010 Sep 8

Fingerprint

Adenosine Deaminase
Motor Neurons
AMPA Receptors
RNA
Oculomotor Nerve
Inosine
Cranial Nerves
RNA Precursors
Amyotrophic Lateral Sclerosis
Ion Channels
Adenosine
Permeability
Epilepsy
Spinal Cord
Alleles
Neurons
Enzymes
Genes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Hideyama, T., Yamashita, T., Suzuki, T., Tsuji, S., Higuchi, M., Seeburg, P. H., ... Kwak, S. (2010). Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. Journal of Neuroscience, 30(36), 11917-11925. https://doi.org/10.1523/JNEUROSCI.2021-10.2010

Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. / Hideyama, Takuto; Yamashita, Takenari; Suzuki, Takeshi; Tsuji, Shoji; Higuchi, Miyoko; Seeburg, Peter H.; Takahashi, Ryosuke; Misawa, Hidemi; Kwak, Shin.

In: Journal of Neuroscience, Vol. 30, No. 36, 08.09.2010, p. 11917-11925.

Research output: Contribution to journalArticle

Hideyama, T, Yamashita, T, Suzuki, T, Tsuji, S, Higuchi, M, Seeburg, PH, Takahashi, R, Misawa, H & Kwak, S 2010, 'Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2', Journal of Neuroscience, vol. 30, no. 36, pp. 11917-11925. https://doi.org/10.1523/JNEUROSCI.2021-10.2010
Hideyama, Takuto ; Yamashita, Takenari ; Suzuki, Takeshi ; Tsuji, Shoji ; Higuchi, Miyoko ; Seeburg, Peter H. ; Takahashi, Ryosuke ; Misawa, Hidemi ; Kwak, Shin. / Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 36. pp. 11917-11925.
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