ALSでみられるユビキチン化封入体の構成蛋白

The Component of Ubiquitin-positive Inclusions in ALS

はじめに

　前頭側頭葉変性症（frontotemporal lobar degeneration: FTLD）に出現するタウ陰性ユビキチン陽性封入体の構成成分として，TAR DNA-binding protein of 43 kDa（TDP-43）が同定された^1，2）。これをきっかけにして，それまで長い間不明であった筋萎縮性側索硬化症（amyotrophic lateral sclerosis: ALS）の変性運動ニューロンに出現するユビキチン陽性封入体の構成蛋白質も，同じTDP-43であることが明らかになった^1，2）。本稿では，ALSにみられるユビキチン陽性構造物について概説するとともに，FTLD，ALSのユビキチン陽性封入体におけるTDP-43の同定の経緯を説明し，ALSとFTLDの関係やALSにおけるTDP-43の蓄積の意義について考察したい。

Abstract

　TAR DNA-binding protein of 43 kDa (TDP-43), a heterogeneous nuclear ribonucleoprotein that functions in regulating transcription and alternative splicing, was identified as a component of ubiquitin-positive tau-negative cytoplasimic inclusions in frontotemporal lobar degeneration (FTLD-U), and subsequently of ubiquitin-positive skein-like inclusions in amyotrophic lateral sclerosis (ALS).　Dephosphorylation treatment of sarkosyl-insoluble fractions have suggested that abnormal phosphorylation takes place in the deposited TDP-43.　The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of TDP-43.　This article reviews the ubiquitin-positive inclusions in ALS and the recent discovery of TDP-43 in tau-negative inclusions in FTLD-U and ALS.　We also discuss the biological implications of these findings for the pathogenesis of ALS.