Original Paper

Acta Neuropathologica

, Volume 120, Issue 1, pp 75-84

First online:

TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2

  • Hitoshi AizawaAffiliated withDivision of Neurology, Department of Internal Medicine, Asahikawa Medical College
  • , Jun SawadaAffiliated withDivision of Neurology, Department of Internal Medicine, Asahikawa Medical College
  • , Takuto HideyamaAffiliated withCREST, Japan Science and Technology Agency, Department of Neurology, Graduate School of Medicine, The University of Tokyo
  • , Takenari YamashitaAffiliated withCREST, Japan Science and Technology Agency, Department of Neurology, Graduate School of Medicine, The University of Tokyo
  • , Takayuki KatayamaAffiliated withDivision of Neurology, Department of Internal Medicine, Asahikawa Medical College
  • , Naoyuki HasebeAffiliated withDivision of Neurology, Department of Internal Medicine, Asahikawa Medical College
  • , Takashi KimuraAffiliated withDepartment of Neurology, Douhoku National Hospital
  • , Osamu YaharaAffiliated withDepartment of Neurology, Douhoku National Hospital
  • , Shin KwakAffiliated withCREST, Japan Science and Technology Agency, Department of Neurology, Graduate School of Medicine, The University of Tokyo Email author 

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Abstract

Both the appearance of cytoplasmic inclusions containing phosphorylated TAR DNA-binding protein (TDP-43) and inefficient RNA editing at the GluR2 Q/R site are molecular abnormalities observed specifically in motor neurons of patients with sporadic amyotrophic lateral sclerosis (ALS). The purpose of this study is to determine whether a link exists between these two specific molecular changes in ALS spinal motor neurons. We immunohistochemically examined the expression of adenosine deaminase acting on RNA 2 (ADAR2), the enzyme that specifically catalyzes GluR2 Q/R site-editing, and the expression of phosphorylated and non-phosphorylated TDP-43 in the spinal motor neurons of patients with sporadic ALS. We found that all motor neurons were ADAR2-positive in the control cases, whereas more than half of them were ADAR2-negative in the ALS cases. All ADAR2-negative neurons had cytoplasmic inclusions that were immunoreactive to phosphorylated TDP-43, but lacked non-phosphorylated TDP-43 in the nucleus. Our results suggest a molecular link between reduced ADAR2 activity and TDP-43 pathology.

Keywords

Amyotrophic lateral sclerosis Adenosine deaminase acting on RNA 2 TDP-43 RNA editing Motor neuron