Nature2014-06-24 4:30 PM

与C9orf72相关神经疾病中的RNA 毒性 C9orf72 nucleotide repeat structures initiate molecular cascades of disease

论文摘要 

重复扩张(指产生一前一后重复的RNA序列的额外版本的突变)是造成40多种遗传疾病的原因,它们一般会导致神经问题和神经肌肉问题。C9orf72六核苷酸重复扩张已被发现是造成“肌萎缩侧索硬化”(ALS)和“额颞痴呆” (FTD)这两种疾病的原因。正常的C9orf72含有多达25个重复片段,而患病者的该基因则会含有数千个。这项研究表明,RNA毒性的增加在ALS/FTD两种疾病中是造成与C9orf72相关病理的原因。转录的C9orf72六核苷酸重复片段被发现以一种依赖于构形的方式与特定的核糖核蛋白如核仁蛋白相结合;因此,核仁蛋白被错误局部化,并且在功能上受损,导致“核仁应激”。

Abstract 

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.

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