• Masato Hasegawa, Takashi Nonaka, Hiroshi Tsuji, Akira Tamaoka, Makiko Yamashita, Fuyuki Kametani, Mari Yoshida, Tetsuaki Arai, and Haruhiko Akiyama.
• Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan. hasegawa-ms@igakuken.or.jp
• J. Mol. Neurosci. 2011 Nov 1;45(3):480-5.

AbstractTDP-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.

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