エリトロミエロイドの祖先の体内の変異が神経変性疾患を引き起こす
Elvira Mass1, Christian E Jacome-Galarza1, Thomas Blank2
1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Nature
|August 31, 2017
まとめ
マクロファージの胎児前駆体におけるソマティックBRAF (V600E) 変異は神経変性を引き起こす. マイクログリアのMAPキナーゼ経路を阻害することで,ニューロンの死が防止され,神経変性疾患に対する新しい治療戦略が提供されます.
科学分野:
- 神経科学
- 遺伝学
- 細胞生物学
背景:
- 神経退行性疾患は,進行性ニューロン喪失と膠質活性化を伴うが,マイクログリアの役割は不明である.
- BRAF (V600E) 変異に関連したヒスティオサイトーズは,骨髄細胞の体内変異が神経変性における役割を果たすことを示唆している.
- マイクログリアは,血液形成性幹細胞とは分離した,固有のエリトロミエロイド原始細胞 (EMP) から発生する.
研究 の 目的:
- EMPの体内のBRAF (V600E) 変異が神経変性を引き起こすかどうかを調査する.
- 神経変性疾患におけるERK活性化マイクログリアの役割を調査する.
- 神経変性疾患の潜在的治療標的を特定する.
主な方法:
- マウスのEMPにおけるBRAF (V600E) のモザイク表現
- マイクログリアの活性化,神経炎症,神経変性マーカーの分析
- 神経行動障害とBRAF抑制の有効性の評価
主要な成果:
- EMPにおけるモザイクBRAF (V600E) 発現はマクロファージのクローン拡張とマウスの重度の遅発性神経変性をもたらした.
- マウスとヒトヒスティオシトーシスの患者で,ERK活性化アミーボイドマイクログリアの蓄積が観察されました.
- 神経行動的欠陥,アストログリオシス,アミロイド前駆体タンパク質の蓄積,シナプス喪失,神経死はERK活性化マイクログリアによって引き起こされた.
- BRAFの阻害はマウスモデルでこれらの病理的アウトカムを防止しました.
結論:
- EMP系統の体内の変異はヒスティオサイトーズの細胞起源であり,遅発の神経変異を引き起こす可能性があります.
- マイクログリアにおけるMAPキナーゼ経路の活性化が神経変性の原因である.
- マイクログリアルMAPキナーゼ経路の活性化をターゲットにすると,神経変性疾患の治療の可能性が生まれます.
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