Acta Neuropathologica

, Volume 120, Issue 1, pp 75–84

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

  • Hitoshi Aizawa
  • Jun Sawada
  • Takuto Hideyama
  • Takenari Yamashita
  • Takayuki Katayama
  • Naoyuki Hasebe
  • Takashi Kimura
  • Osamu Yahara
  • Shin Kwak
Original Paper

DOI: 10.1007/s00401-010-0678-x

Cite this article as:
Aizawa, H., Sawada, J., Hideyama, T. et al. Acta Neuropathol (2010) 120: 75. doi:10.1007/s00401-010-0678-x

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 sclerosisAdenosine deaminase acting on RNA 2TDP-43RNA editingMotor neuron

Supplementary material

401_2010_678_MOESM1_ESM.ppt (2.2 mb)
Supplementary Figure 1ADAR2 immunostaining in degenerating neurons in other neurological diseases. Neurons in the pontine nuclei of an ALS patient exhibit slight ADAR2 immunoreactivity in the cytoplasm (a). The neurons in the pontine nuclei in both multiple system atrophy (b) and spinocerebellar atrophy type 1 (c) showed faint ADAR2 immunoreactivity, although these neurons were atrophic and reduced in number. These results suggested that the alteration of ADAR2 activity was not involved in the process of neuronal death in the pontine nucleus of MSA or SCA1. Bar indicates 20 μm (PPT 2238 kb)
401_2010_678_MOESM2_ESM.ppt (1.8 mb)
Supplementary Figure 2Immunohistochemistry with two anti-ADAR2 antibodies. Both RED1 (a) and C-15 (b) stained specifically the cytoplasm but not the nucleus of motor neurons. Non-specific lipofuscin staining is observed in (b) (PPT 1858 kb)
401_2010_678_MOESM3_ESM.doc (24 kb)
Supplementary material 3 (DOC 24 kb)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Hitoshi Aizawa
    • 1
  • Jun Sawada
    • 1
  • Takuto Hideyama
    • 2
  • Takenari Yamashita
    • 2
  • Takayuki Katayama
    • 1
  • Naoyuki Hasebe
    • 1
  • Takashi Kimura
    • 3
  • Osamu Yahara
    • 3
  • Shin Kwak
    • 2
  1. 1.Division of Neurology, Department of Internal MedicineAsahikawa Medical CollegeAsahikawaJapan
  2. 2.CREST, Japan Science and Technology Agency, Department of Neurology, Graduate School of MedicineThe University of TokyoTokyoJapan
  3. 3.Department of NeurologyDouhoku National HospitalAsahikawaJapan