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Glutamine/arginine site-unedited GluA2 mRNA in cerebrospinal fluid as a biomarker for amyotrophic lateral sclerosis
  1. Takashi Hosaka1,2,3,
  2. Hiroshi Tsuji1,
  3. Makoto Terada1,2,3,
  4. Yasushi Tomidokoro1,
  5. Akiko Ishii1,
  6. Kiyotaka Nakamagoe1,
  7. Kazuhiro Ishii1,
  8. Hiroo Terashi4,
  9. Hitoshi Aizawa4,5,
  10. Akira Tamaoka1,
  11. Shin Kwak4,5
  1. 1 Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  2. 2 University of Tsukuba Hospital/Jichi Medical University Joint Ibaraki Western Regional Clinical Education Center, Chikusei, Japan
  3. 3 Internal Medicine, Ibaraki Western Medical Center, Chikusei, Japan
  4. 4 Department of Neurology, Tokyo Medical University, Tokyo, Japan
  5. 5 Department of Molecular Neuropathogenesis (Endowed Chair, GTRI), Tokyo Medical University, Tokyo, Japan
  1. Correspondence to Professor Shin Kwak, Department of Neurology, Tokyo Medical University, Shinjuku-ku, 160-8402, Japan; kwak{at}

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Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease with diverse clinical manifestations and progression speed among patients.1 Reliable diagnostic biomarkers for sporadic ALS are currently lacking, leading to delayed diagnosis. Therefore, developing disease-specific diagnostic biomarkers reflecting ALS processes is a critical unmet medical need. Moreover, biomarkers predicting treatment efficacy are required, given the increasing number of clinical trials investigating potential therapies resulting from the increase in knowledge regarding ALS pathogenesis.1

Excitotoxicity or dysregulation of glutamatergic signalling has long been considered a plausible mechanism underlying motor neuron death in both sporadic and familial ALS.1 In healthy neurons, the glutamine/arginine (Q/R) site of all expressed GluA2, a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, is subjected to RNA editing by adenosine deaminase acting on RNA 2 (ADAR2), which catalyses adenosine-to-inosine conversion of premessenger RNA.1 In the lower motor neurons of patients with sporadic ALS, Q/R site-unedited GluA2 mRNA is expressed due to ADAR2 downregulation,2 resulting in AMPA receptor-mediated death of motor neurons.1 Transactive response DNA-binding protein of 43 kDa (TDP-43) pathology, the pathological hallmark of ALS, invariably colocalises with ADAR2 deficiency in the spinal motor neurons of patients with sporadic ALS.3 Therefore, Q/R site-unedited GluA2 expression due to ADAR2 downregulation is involved in sporadic ALS pathogenesis.

We previously demonstrated that editing efficiency at the Q/R site of extracellular GluA2 mRNA reflects intracellular ADAR2 activity in cultured cells,4 suggesting that ADAR2 activity in the lower motor neurons can be estimated by analysing the editing efficiency of extracellular GluA2 mRNA. Herein, we compared the editing efficiency of GluA2 mRNA in the cerebrospinal fluid (CSF) between patients with sporadic ALS and patients with non-ALS diseases and analysed the correlation between editing efficiency and clinical parameters of ALS symptoms.


This multicentric, prospective observational study included 31 patients …

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  • Contributors TH: conceptualisation, resources, data curation, formal analysis, funding acquisition, validation, investigation, visualisation, methodology and writing (original draft, review and editing). HTs: conceptualisation, resources, data curation, supervision, funding acquisition, investigation, methodology and writing (review and editing). MT and HA: resources, data curation, investigation and writing (review and editing). YT, AI, KN, KI, HTe and AT: resources, investigation and writing (review and editing). SK: conceptualisation, supervision, validation, visualisation, methodology, project administration and writing (review and editing).

  • Funding This research was supported by JSPS KAKENHI (grant numbers 19K23957 and 21K15178), the Uehara Memorial Foundation (grant number 202010135), the Yukihiko Miyata Memorial Trust For ALS Research and the GSK Japan Research Grant 2017.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.