[Significance of the TDP-43 deposition in FTLD-U and ALS].
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
Hasegawa
Masato
M
Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research.
Arai
Tetsuaki
T
Nonaka
Takashi
T
Kametani
Fuyuki
F
Yoshida
Mari
M
Hashizume
Yoshio
Y
Beach
Thomas G
TG
Morita
Mitsuya
M
Nakano
Imaharu
I
Oda
Tatsuro
T
Tsuchiya
Kuniaki
K
Akiyama
Haruhiko
H
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000906:Antibodies; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology; D003704:Dementia / Q000235:genetics*; D006801:Humans; D045586:Intranuclear Inclusion Bodies; D009154:Mutation; D009842:Oligopeptides; D025801:Ubiquitin
D000906:Antibodies; D004268:DNA-Binding Proteins; D009842:Oligopeptides; D025801:Ubiquitin; C118151:phosphoTyr-Glu-Glu-Ile-NH2