ヘリカーゼはヘクサヌクレオチド重複RNAのG四重複を解き放ち,重複関連非AUG翻訳を容易にする
Honghe Liu1,2, Yu-Ning Lu1,2, Tapas Paul3
1Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, United States.
Journal of the American Chemical Society
|April 15, 2021
まとめ
RNAヘリケーズDHX36は,重複RNAのG四重複構造を解き放つことで,C9orf72結合ALSおよびFTDにおける毒性タンパク質の生成を促進する. DHX36を減少させると これらの有毒なタンパク質が減り 治療の標的となるのです
科学分野:
- 神経科学
- 分子生物学
- 遺伝学
背景:
- C9orf72遺伝子のヘクサヌクレオチド再発は,ALSとFTDの主な原因である.
- リピート関連非AUG (RAN) 翻訳は毒性ダイペプチドリピート (DPR) タンパク質を生成するが,その調節は不明である.
研究 の 目的:
- C9orf72のリピート関連RAN翻訳におけるRNAヘリケーズDHX36の役割を調査する.
- DHX36がC9orf72関連ALSおよびFTDの潜在的治療標的であるかどうかを判断する.
主な方法:
- G4C2リピートRNAに対するDHX36結合親和性と解き放つ活性が評価された.
- DHX36とG4C2RNAの相互作用を細胞モデルで調べました.
- 患者に由来するiPSCと運動ニューロンのDHX36濃度が低下した.
- 変化したDHX36発現の細胞におけるDPRタンパク質濃度測定
- 患者の組織におけるDHX36発現を分析した.
主要な成果:
- DHX36はG4C2リピートRNA,特にG-四重複形に結合し,これらの構造を解き放ちます.
- DHX36はC9orf72 RAN翻訳に不可欠である.
- DHX36を患者の細胞で減少させると,DPRタンパク質の濃度が低下した.
- DHX36はC9orf72に結合したALS患者の組織で上位調節される.
結論:
- DHX36は,G四重複構造を解除することによって,C9orf72 RAN変換の正の調節剤として作用する.
- DHX36はC9orf72関連ALSとFTDの潜在的な治療標的である.
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