BRAIN and NERVE－神経研究の進歩59巻10号

2007年10月発行

増大特集 ALS―研究と診療の進歩

近位軸索損傷モデルにおける運動神経細胞変性と治療

著者： 渡部和彦¹

所属機関： ¹財団法人東京都医学研究機構東京都神経科学総合研究所神経細胞機能研究分野分子神経病理研究部門

ページ範囲：P.1179 - P.1186

文献概要

はじめに

　筋萎縮性側索硬化症（ALS）における運動ニューロン死には，活性酸素・窒素種の関与や，細胞体内のニューロフィラメントの蓄積と軸索輸送の障害，ミトコンドリアの障害，グルタミン酸と興奮毒性の関与，ユビキチン・プロテアソーム系の機能障害など，さまざまな病態メカニズムが指摘されているが，その一次的な病態は依然として解明されていない^1）。ALSのうち，約10％を占める家族性ALSの病因の一部（全体の2％）にCu/Zn superoxide dismutase（SOD1）遺伝子変異が知られて以来，ヒト変異SOD1トランスジェニック・マウス，ラットがALSの病態解明と治療法の研究に大きく寄与している。しかし大多数を占める孤発性ALSの病因はなお不明であり，変異SOD1マウスがその理想的なモデルであるとは言い難い。一方，運動神経損傷により運動ニューロン死が惹起されるが，その一次的病因はALSとはもちろん異なっているものの，運動ニューロンが死に至る像はよく類似しており，これまでに軸索損傷実験の報告が多数蓄積されている^2，3）。このうち成体運動ニューロン死のモデルとして，成体げっ歯類の近位軸索損傷，すなわち末梢神経引き抜き損傷がある。本動物モデルの運動ニューロン変性パターンは新生仔と異なって比較的長期間の経過をたどり，これまでに活性酸素・窒素種の関与や，細胞体におけるニューロフィラメントの蓄積が報告されており，ヒトALSとの形態学的，生化学的類似点が多い。本稿では，成体ラットの末梢神経引き抜き損傷モデルを用いた運動ニューロン損傷の解析と治療法のアプローチについて概説する。

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