ALS-FTDでは,保存されていない暗号エクソンのTDP-43抑制が損なわれています

Jonathan P Ling¹, Olga Pletnikova¹, Juan C Troncoso²

¹Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.

Science (New York, N.Y.)

|August 8, 2015

まとめ

TDP-43タンパク質は通常,暗号的なエクソンスプライシングを抑制する. 細胞内のTDP-43の喪失は, ALS-FTDで見られる欠陥である細胞死を引き起こす神秘的なエクソン含有につながります.

科学分野:

神経科学
分子生物学
遺伝学

背景:

TDP-43の細胞プラズマ集積は,アミオトロフィック横筋硬化症と前頭葉性認知症 (ALS-FTD) の特徴です.
RNAスプライシングにおけるTDP-43の正確な機能と,神経変性疾患の病原性におけるその役割は,まだ完全に理解されていません.
TDP-43の機能を理解することは,TDP-43のタンパク質病変のメカニズムを明らかにするために不可欠です.

研究の目的:

TDP-43のRNAスプライシングにおける役割を調査し,特に保存されていない暗号エクソンに焦点を当てます.
TDP-43によるスプライシングの欠陥がALS-FTDの病理に寄与するかどうかを判断する.

主な方法:

マウスの胚性幹細胞におけるTDP-43の減少
暗号的なエクソン含有を含むメッセンジャーRNAのスプライシングパターンの分析.
細胞活性の評価と無意味な媒介による腐敗の経路
患者からのALS-FTDサンプルにおける暗号的エクソンスプライシングの検査

主要な成果:

TDP-43は,保存されていない暗号エクソンのスプライシングを抑制し,それによってイントロンの完全性を維持することが判明した.
TDP-43の枯渇は,暗号的エクソンがメッセンジャーRNAにスプライスされ,しばしばトランスレーション障害とナンセンス媒介の衰退を引き起こした.
TDP-43欠乏した細胞の細胞死を防ぐ.
ALS- FTD患者のサンプルでは,暗号的エクソンの抑制が低下したことが観察されました.

結論:

TDP-43は,暗号的なエクソンスプライシングを抑制する上で重要な役割を果たします.
ALS-FTDにおけるTDP-43タンパク質病変の根本的なメカニズムは,暗号的なエクソンを含むスプライシングの欠陥である可能性があります.
ALS-FTDの潜在的な治療法です

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