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Journal of Molecular Neuroscience

, Volume 45, Issue 3, pp 480–485 | Cite as

Molecular Dissection of TDP-43 Proteinopathies

  • Masato HasegawaEmail author
  • Takashi Nonaka
  • Hiroshi Tsuji
  • Akira Tamaoka
  • Makiko Yamashita
  • Fuyuki Kametani
  • Mari Yoshida
  • Tetsuaki Arai
  • Haruhiko Akiyama
Article

Abstract

TDP-43 has been identified as a major component of ubiquitin-positive tau-negative cytoplasmic inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS). We raised antibodies to phosphopeptides representing 36 out of 64 candidate phosphorylation sites of human TDP-43 and showed that the antibodies to pS379, pS403/404, pS409, pS410 and pS409/410 labeled the inclusions, but not the nuclei. Immunoblot analyses demonstrated that the antibodies recognized TDP-43 at ~45 kDa, smearing substances and 18–26 kDa C-terminal fragments. Furthermore, the band patterns of the C-terminal fragments differed between neuropathological subtypes, but were indistinguishable between brain regions and spinal cord in each individual patient. Protease treatment of Sarkosyl-insoluble TDP-43 suggests that the different band patterns of the C-terminal fragments reflect different conformations of abnormal TDP-43 molecules between the diseases. These results suggest that molecular species of abnormal TDP-43 are different between the diseases and that they propagate from affected cells to other cells during disease progression and determine the clinicopathological phenotypes of the diseases.

Keywords

Propagation Phosphorylation Tau α-Synuclein Prion Cancer 

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Masato Hasegawa
    • 1
    • 2
    Email author
  • Takashi Nonaka
    • 1
    • 2
  • Hiroshi Tsuji
    • 1
    • 3
  • Akira Tamaoka
    • 3
  • Makiko Yamashita
    • 1
    • 2
  • Fuyuki Kametani
    • 1
    • 2
  • Mari Yoshida
    • 4
  • Tetsuaki Arai
    • 2
    • 5
  • Haruhiko Akiyama
    • 2
  1. 1.Department of Neuropathology and Cell BiologyTokyo Metropolitan Institute of Medical ScienceTokyoJapan
  2. 2.Dementia Research ProjectTokyo Metropolitan Institute of Medical ScienceTokyoJapan
  3. 3.Department of Neurology, Graduate School of Comprehensive Human SciencesUniversity of TsukubaIbarakiJapan
  4. 4.Department of Neuropathology, Institute for Medical Science of AgingAichi Medical UniversityAichiJapan
  5. 5.Department of Psychiatry, Graduate School of Comprehensive Human SciencesUniversity of TsukubaIbarakiJapan

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