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