1] Department of Biochemistry and Molecular Biology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] Department of Neuroscience, Johns Hopkins University Baltimore, Maryland 21205, USA.
1] Department of Neurology, Johns Hopkins University Baltimore, Maryland 21205, USA [2] The Brain Science Institute, Johns Hopkins University Baltimore, Maryland 21205, USA.
Nature. 2014 Mar 13;507(7491):195-200. doi: 10.1038/nature13124. Epub 2014 Mar 5.
A hexanucleotide repeat expansion (HRE), (GGGGCC)n, in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA•DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.
六核苷酸重复扩展（HRE）（GGGGCC）n 在 C9orf72 中是引起神经退行性疾病肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的最常见遗传原因。在这里，我们确定了结构多态性导致 ALS/FTD 病理学和缺陷的分子机制。HRE 形成具有不同结构的 DNA 和 RNA G-四联体，并促进 RNA•DNA 杂交（R 环）。结构多态性导致在 HRE 区域中截短的转录物的重复长度依赖性积累。这些转录重复以构象依赖性的方式与核糖核蛋白结合。具体而言，核仁蛋白（nucleolin）是一种必需的核仁蛋白，优先结合 HRE G-四联体，并且患者细胞显示出核仁应激的证据。我们的结果表明，在 DNA 和 RNA 水平上的不同 C9orf72 HRE 结构多态性引发了导致 ALS/FTD 病理学的分子级联反应，并为重复相关神经退行性疾病的机制模型提供了基础。
