Rinsho Shinkeigaku (Clinical Neurology)

The 49th Annual Meeting of the Japanese Society of Neurology

The significance of the TDP-43 deposition in FTLD-U and ALS

Masato Hasegawa, M.D.1), Tetsuaki Arai, M.D.2), Takashi Nonaka, M.D.1), Fuyuki Kametani, M.D.1), Mari Yoshida, M.D.3), Yoshio Hashizume, M.D.3), Thomas G Beach, M.D.4), Mitsuya Morita, M.D.5), Imaharu Nakano, M.D.5), Tatsuro Oda, M.D.6), Kuniaki Tsuchiya, M.D.7) and Haruhiko Akiyama, M.D.2)

1)Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research
2)Department of Psychogeriatrics, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research
3)Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University
4)Sun Health Research Institute
5)Department of Neurology, Jichi Medical University
6)Department of Neuropsychiatry, National Shimofusa Mental Hospital
7)Department of Laboratory Medicine and Pathology, Tokyo Metropolitan Matsuzawa Hospital

Tau-negative and ubiquitin-positive inclusions (UPI) are the pathological hallmarks of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). Recently, TDP-43, a heterogeneous nuclear ribonucleoprotein was identified as a component of these UPI. However, it remains to be determined whether TDP-43 is the major component of UPI, because only antibodies recognizing both normal and abnormal TDP-43 have been available. We raised antibodies to phosphopeptides representing 36 out of 64 candidate phosphorylation sites of human TDP-43. Of the generated antibodies, pS379, pS403/404, pS409, pS410 and pS409/410 clearly labeled UPI and glial cytoplasmic inclusions but not the nuclei. Immunoblot analyses of sarkosyl insoluble fractions demonstrated that the phosphorylation-specific antibodies recognized TDP-43 at -45 kDa, smearing substances and the -25 kDa fragment, all of which were present in the brains of FTLD-U and ALS but not controls. These antibodies did not recognize normal TDP-43 at 43 kDa. These results clearly indicate that abnormally phosphorylated full-length TDP-43 and the C-terminal fragments are the major component of UPI in FTLD-U and ALS. These findings together with recent discovery of mutations in the TDP-43 gene in ALS strongly suggest that TDP-43 is the key molecule responsible for neurodegeneration in FTLD-U and ALS.
Full Text of this Article in Japanese PDF (425K)

(CLINICA NEUROL, 48: 994|997, 2008)
key words: ubiquitin, tau, phosphorylation, fragment, ALS

(Received: 17-May-08)