一个螺旋酶解开六核酸重复RNA G-四重复,并促进重复关联的非AUG翻译
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
概括
在C9orf72相关的ALS和FTD中,RNA螺旋酶DHX36通过在重复RNA中解G四重复结构来促进有毒蛋白质的产生. 减少DHX36降低了这些有毒的蛋白质,
科学领域:
- 神经科学
- 分子生物学
- 遗传学
背景情况:
- C9orf72基因的重复扩张是ALS和FTD的主要原因.
- 重复关联的非AUG (RAN) 翻译产生有毒的二重复 (DPR) 蛋白质,但其调节不清楚.
研究的目的:
- 调查RNA酶DHX36在C9orf72重复关联RAN转化中的作用.
- 确定DHX36是否是C9orf72相关的ALS和FTD的潜在治疗标.
主要方法:
- 在G4C2重复RNA上评估了DHX36的结合亲和力和解活性.
- 在细胞模型中检查了DHX36与G4C2RNA的相互作用.
- 在患者衍生的iPSC和运动神经元中降低了DHX36水平.
- 在改变DHX36表达的细胞中测量DPR蛋白水平.
- 分析患者组织中的DHX36表达.
主要成果:
- DHX36结合G4C2重复RNA,特别是其G-四重复的形式,并解开这些结构.
- DHX36对于C9orf72的RAN转换至关重要.
- 在患者细胞中降低DHX36降低了DPR蛋白水平.
- 在C9orf72结合的ALS患者组织中,DHX36的调节升高.
结论:
- DHX36通过解决G-四重复结构,作为C9orf72RAN转换的积极调节者.
- 对于C9orf72相关的ALS和FTD,DHX36是潜在的治疗点.
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