C9orf72核酸重复结构启动疾病的分子级联
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
概括
六核酸C9orf72的重复扩张是ALS和FTD的原因,形成了不同的DNA/RNA结构. 这种结构多态导致重复积累,核结合和核细胞应激,驱动神经退行性病理.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
背景情况:
- 肌缩侧面硬化症 (ALS) 和前性痴呆症 (FTD) 是常见的神经退行性疾病.
- 在C9orf72基因中,六核酸重复扩张 (HRE) 是ALS和FTD最常见的遗传原因.
研究的目的:
- 阐明将C9orf72 HRE结构多态与ALS/FTD病理联系起来的分子机制.
- 调查HRE结构变异如何启动疾病特异性的分子级联.
主要方法:
- 对由HRE.形成的DNA和RNAG-四重复结构的分析.
- 研究RNA•DNA杂交 (R-循环) 的形成.
- 评估重复的转录积累和核蛋白结合.
- 对HRE G四重复合物的核结合的评估.
- 检查患者衍生细胞中核应激的情况.
主要成果:
- HRE结构多态性导致不同的DNA和RNAG四重复,并促进R循环.
- 在HRE区域内,中断的转录的重复长度依赖积累.
- 转录的重复的依赖于形态的结合与核糖核蛋白,特别是核.
- 在患有C9orf72 HRE.的ALS/FTD患者的细胞中发现核应激的证据.
结论:
- 在DNA和RNA两种层面上,C9orf72 HRE的独特结构多态化启动了驱动ALS/FTD的分子级联.
- 这项研究为像ALS和FTD这样的重复相关的神经退行性疾病提供了一种机制模型.
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