C9orf72の反復膨張は核細胞の輸送を妨害する
Ke Zhang1, Christopher J Donnelly2, Aaron R Haeusler3
1Department of Neurology, School of Medicine, Johns Hopkins University.
Nature
|August 27, 2015
まとめ
C9orf72のGGGGCCの繰り返し拡大はALSとFTDを引き起こす. 研究者らは,リピートRNAを標的にして,核細胞質の輸送欠陥を修正することで,これらの神経変性疾患を治療できることを発見しました.
科学分野:
- 神経科学
- 遺伝学
- 分子生物学
背景:
- C9orf72ヘクサヌクレオチド再発 (HRE) は,アミオトロフィック横筋硬化症 (ALS) とフロントテンポラル認知症 (FTD) の主要な遺伝的原因である.
- 以前の研究では,HRE RNAを含む有毒な機能増強メカニズムが示唆されており,RanGAP1が潜在的相互作用因子として特定されています.
研究 の 目的:
- C9orf72に関連した神経変性における核細胞質輸送の役割を調査する.
- C9orf72変異に関連したALSとFTDの治療標的を特定する.
主な方法:
- ドロソフィラの遺伝子スクリーンは,HRE誘発の神経変性抑制剤としてRanGAPを特定しました.
- HRE RNA と RanGAP の相互作用を調査した.
- HRE発現するハエ,患者からのニューロン,脳組織における核細胞質輸送を調査した.
- 小分子と反意味オリゴヌクレオチドをテストして 輸送障害を修復する
主要な成果:
- 核細胞プラズマ輸送調節剤であるRanGAPは,ハエのモデルでHRE媒介の神経変性を抑制する.
- RanGAPはHRE RNAと物理的に相互作用し,ハエのモデルと患者由来の細胞/組織で誤局所化を示しています.
- この赤字は,HRE G四重複体をターゲットにすることで救済されます.
結論:
- 核サイトプラズマ輸送欠陥は,C9orf72 ALSとFTDにおける重要な病原性経路である.
- これらの輸送欠陥をターゲットにすることで これらの破壊的な神経変性疾患に対する 有望な薬剤療法戦略が提供されます
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