MAPKのカスケードによる病理的な軸索死は,局所的なエネルギー赤字を誘発する
Jing Yang1, Zhuhao Wu1, Nicolas Renier1
1Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA.
Cell
|January 17, 2015
まとめ
神経退行性疾患の特徴である軸索変性には,軸索エネルギーを枯渇させる,新たに特定されたSarm1-MAPK経路が含まれています. cytoNmnat1/Wld(s) とAKTシグナル伝達などの保護性タンパク質は,この経路を調節する.
科学分野:
- 神経科学は神経科学である.
- 分子生物学は分子生物学である.
- 細胞生物学 細胞生物学
背景:
- 軸索死は神経回路の接続性を損なっており,神経変性疾患の中心にある.
- プログラムされた細胞死とは無関係な病理的な軸索変性メカニズムは,ほとんど不明である.
研究 の 目的:
- 軸索損傷におけるミトゲン活性化タンパク質キナーゼ (MAPK) 家族を調査する.
- 初期の軸索変性反応に関与する分子カスケードを描画する.
主な方法:
- トラウマ性軸索損傷モデルを利用した.
- 系統的に調査されたMAPKファミリー.
- Sarm1,cytoNmnat1/Wld(s),MKK4,AKT,およびJNKのシグナリングの役割を調べました.
主要な成果:
- 軸索損傷に対する早期の反応として,Sarm1-依存のMAPKカスケードを特定しました.
- この経路が軸索のエネルギーホメオスタシスを破壊し,ATPの枯渇を引き起こすことを実証しました.
- cytoNmnat1/Wld(s) がMAPKカスケードを阻害し,AKTシグナリングがMKK4を敵対してJNKシグナリングを調節することを発見した.
結論:
- 病理的な軸索変性におけるSarm1-MAPK,cytoNmnat1/Wld(s,AKT/JNKのシグナリングを統合する規制メカニズムを明らかにした.
- この経路は,損傷後の軸索の整合性を決定する重要な決定因子です.
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