Departments of Pharmacology and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Cell Biology, UT Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
Cell Chem Biol. 2017 Feb 16;24(2):141-148. doi: 10.1016/j.chembiol.2016.12.018. Epub 2017 Jan 26.
The chromosome 9 open reading frame 72 (c9orf72) gene contains a hexanucleotide (GGGGCC) repeat expansion responsible for many cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mutant intronic RNA forms "foci" within nuclei, but the connection between transcript expression, foci, and biochemical disease mechanisms is unclear. Knowing the absolute numbers of cellular RNAs, in any system, is important for understanding the molecular mechanisms of natural physiology, disease, and drug action. Absolute numbers, however, are rarely determined, and this absence is a major impediment to understanding complex systems. Using quantitative methods, we demonstrate that foci are single RNA molecules. Most cells have no foci while 1%-2% have more than ten. Knowing the number of disease-causing molecules may contribute to understanding ALS and FTD pathology and successful drug discovery. More broadly, our data suggest that small numbers of RNA molecules may have a sizable impact on disease.
染色体 9 开放阅读框 72（c9orf72）基因包含一个六核苷酸（GGGGCC）重复扩展，负责许多肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）病例。突变的内含子 RNA 在核内形成“焦点”，但转录表达、焦点和生化疾病机制之间的联系尚不清楚。了解任何系统中细胞 RNA 的绝对数量对于理解自然生理学、疾病和药物作用的分子机制很重要。然而，绝对数量很少被确定，这是理解复杂系统的主要障碍。我们使用定量方法证明焦点是单个 RNA 分子。大多数细胞没有焦点，而 1%-2%的细胞有超过十个焦点。了解致病分子的数量可能有助于理解 ALS 和 FTD 的病理学和成功的药物发现。更广泛地说，我们的数据表明，少量的 RNA 分子可能对疾病有相当大的影响。
