第49回日本神経学会総会
＜シンポジウム9-2＞前頭側頭型認知症（FTD）をめぐる基礎と臨床の最前線
FTDにおけるTDP-43蓄積の意義
長谷川 成人1）, 新井 哲明1）, 野中 隆1）, 亀谷 富由樹1）, 吉田 眞理2）, 橋詰 良夫2）, Thomas Beach3）, 森田 光哉4）, 中野 今治4）, 織田 辰郎5）, 土谷 邦秋6）, 秋山 治彦1）
1）東京都精神医学総合研究所〔〒156-8585 東京都世田谷区上北沢2-1-8〕
2）愛知医科大学加齢医科学研究所
3）Sun Health Research Institute
4）自治医科大学神経内科
5）下総精神医療センター
6）都立松沢病院検査科
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)
(臨床神経, 48：994−997, 2008)
key words：ユビキチン, タウ, リン酸化, 断片, ALS
（受付日：2008年5月17日）
