title: [Significance of the TDP-43 deposition in FTLD-U and ALS].
abstract: 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
authors.affiliation: Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Arai
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Kametani
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hashizume
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.forename: Mitsuya
authors.initials: M
authors.lastname: Morita
authors.forename: Imaharu
authors.initials: I
authors.lastname: Nakano
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Oda
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
mesh_terms: 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
chemical_list: D000906:Antibodies; D004268:DNA-Binding Proteins; D009842:Oligopeptides; D025801:Ubiquitin; C118151:phosphoTyr-Glu-Glu-Ile-NH2