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Title: TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Abstract

Ubiquitin-positive tau-negative neuronal cytoplasmic inclusions and dystrophic neurites are common pathological features in frontotemporal lobar degeneration (FTLD) with or without symptoms of motor neuron disease and in amyotrophic lateral sclerosis (ALS). Using biochemical and immunohistochemical analyses, we have identified a TAR DNA-binding protein of 43 kDa (TDP-43), a nuclear factor that functions in regulating transcription and alternative splicing, as a component of these structures in FTLD. Furthermore, skein-like inclusions, neuronal intranuclear inclusions, and glial inclusions in the spinal cord of ALS patients are also positive for TDP-43. Dephosphorylation treatment of the sarkosyl insoluble fraction has shown that abnormal phosphorylation takes place in accumulated TDP-43. The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of TDP-43.

Authors:
 [1];  [2];  [3];  [4];  [5];  [6];  [7];  [8];  [9];  [9];  [10]
  1. Department of Psychogeriatrics, Tokyo Institute of Psychiatry 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585 (Japan). E-mail: arai@prit.go.jp
  2. Department of Molecular Neurobiology, Tokyo Institute of Psychiatry 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585 (Japan). E-mail: masato@prit.go.jp
  3. Department of Psychogeriatrics, Tokyo Institute of Psychiatry 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585 (Japan)
  4. Zikei hospital 100-2 Urayasuhonmachi, Okayama-shi, Okayama 702-8508 (Japan)
  5. Department of Molecular Neurobiology, Tokyo Institute of Psychiatry 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585 (Japan)
  6. Department of Neuroscience, Osaka City University School of Medicine, 1-4-3 Asahimachi, Abenoku, Osaka 545-8585 (Japan)
  7. Greater Manchester Neurosciences Centre, University of Manchester, Hope Hospital, Salford M6 8HD (United Kingdom)
  8. Department of Laboratory Medicine and Pathology, Tokyo Metropolitan Matsuzawa Hospital, 2-1-1 Kamikitazawa, Setagaya-ku, Tokyo 156-0057 (Japan)
  9. Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, 21 Karimata, Yazako, Nagakute-cho, Aichi-gun, Aichi 480-1195 (Japan)
  10. Department of Neuropsychiatry, National Shimofusa Mental Hospital, Chiba 266-0007 (Japan)
Publication Date:
OSTI Identifier:
20857924
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 351; Journal Issue: 3; Other Information: DOI: 10.1016/j.bbrc.2006.10.093; PII: S0006-291X(06)02318-7; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; DNA; MASS SPECTROSCOPY; NERVE CELLS; NERVOUS SYSTEM DISEASES; PHOSPHORYLATION; PROTEINS; SPINAL CORD; SPLICING; SYMPTOMS; TAR; TRANSCRIPTION

Citation Formats

Arai, Tetsuaki, Hasegawa, Masato, Akiyama, Haruhiko, Ikeda, Kenji, Nonaka, Takashi, Mori, Hiroshi, Mann, David, Tsuchiya, Kuniaki, Yoshida, Mari, Hashizume, Yoshio, and Oda, Tatsuro. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. United States: N. p., 2006. Web. doi:10.1016/j.bbrc.2006.10.093.
Arai, Tetsuaki, Hasegawa, Masato, Akiyama, Haruhiko, Ikeda, Kenji, Nonaka, Takashi, Mori, Hiroshi, Mann, David, Tsuchiya, Kuniaki, Yoshida, Mari, Hashizume, Yoshio, & Oda, Tatsuro. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. United States. doi:10.1016/j.bbrc.2006.10.093.
Arai, Tetsuaki, Hasegawa, Masato, Akiyama, Haruhiko, Ikeda, Kenji, Nonaka, Takashi, Mori, Hiroshi, Mann, David, Tsuchiya, Kuniaki, Yoshida, Mari, Hashizume, Yoshio, and Oda, Tatsuro. Fri . "TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis". United States. doi:10.1016/j.bbrc.2006.10.093.
@article{osti_20857924,
title = {TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis},
author = {Arai, Tetsuaki and Hasegawa, Masato and Akiyama, Haruhiko and Ikeda, Kenji and Nonaka, Takashi and Mori, Hiroshi and Mann, David and Tsuchiya, Kuniaki and Yoshida, Mari and Hashizume, Yoshio and Oda, Tatsuro},
abstractNote = {Ubiquitin-positive tau-negative neuronal cytoplasmic inclusions and dystrophic neurites are common pathological features in frontotemporal lobar degeneration (FTLD) with or without symptoms of motor neuron disease and in amyotrophic lateral sclerosis (ALS). Using biochemical and immunohistochemical analyses, we have identified a TAR DNA-binding protein of 43 kDa (TDP-43), a nuclear factor that functions in regulating transcription and alternative splicing, as a component of these structures in FTLD. Furthermore, skein-like inclusions, neuronal intranuclear inclusions, and glial inclusions in the spinal cord of ALS patients are also positive for TDP-43. Dephosphorylation treatment of the sarkosyl insoluble fraction has shown that abnormal phosphorylation takes place in accumulated TDP-43. The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of TDP-43.},
doi = {10.1016/j.bbrc.2006.10.093},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 351,
place = {United States},
year = {Fri Dec 22 00:00:00 EST 2006},
month = {Fri Dec 22 00:00:00 EST 2006}
}