C9orf72ヌクレオチドの重複構造は,疾患の分子カスケードを開始します
Aaron R Haeusler1, Christopher J Donnelly2, Goran Periz1
11] Department of Biochemistry and Molecular Biology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] Department of Neuroscience, Johns Hopkins University Baltimore, Maryland 21205, USA.
Nature
|March 7, 2014
まとめ
ALSとFTDの原因であるC9orf72ヘクサヌクレオチドの繰り返し膨張は,独特のDNA/RNA構造を形成する. この構造的多形性は,繰り返し蓄積,ヌクレオリン結合,および核性ストレスにつながり,神経変性病理を誘発します.
科学分野:
- 神経科学は神経科学である.
- 遺伝学 遺伝学とは
- 分子生物学は分子生物学である.
背景:
- 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) は一般的な神経変性疾患です.
- C9orf72遺伝子のヘクサヌクレオチド再発拡張 (HRE) は,ALSとFTDの最も頻繁な遺伝的原因です.
研究 の 目的:
- C9orf72 HRE構造的多形性をALS/FTD病理と結びつける分子メカニズムを解明する.
- HREの構造的変異が疾患特有の分子カスケードをどのように開始するかを調査する.
主な方法:
- HREによって形成されたDNAとRNAのG四重複構造の分析.
- RNA•DNAハイブリッド (R-ループ) 形成の調査.
- リピートトランスクリプトの蓄積とリボヌクレオプロテイン結合の評価.
- HRE G四重複合体へのヌクレオリン結合の評価.
- 患者から派生した細胞における核ストレスの検査.
主要な成果:
- HREの構造的ポリモルフィズムにより,DNAとRNAのG四重複体が区別され,Rループが促進される.
- HRE領域内の中断されたトランスクリプトの繰り返し長さ依存の蓄積.
- 転写されたリピートの形状に依存した結合は,リボヌクレオプロテイン,特にヌクレオリンと結合する.
- C9orf72 HRE.のALS/FTD患者からの細胞における核ストレスの証拠
結論:
- DNAとRNAの両方のレベルでC9orf72 HREの独特の構造的多形態化は,ALS/FTDを駆動する分子カスケードを開始します.
- この研究は,ALSやFTDのような繰り返し関連性神経変性疾患のメカニズムモデルを提供します.
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