G-quadruplex Structures as Targets and Tools in ALS

 描述（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，目前无法治愈。我们拟研究G-四链体（G4）结构和G4组装分子在神经退行性变和ALS发病机制中的作用。G4是与多种生物过程相关的独特结构，包括遗传不稳定性、基因表达的转录和转录后调控。我们以前已经确定了新的应激反应途径，这是由核糖核酸酶血管生成素（ANG）通过切割细胞质tRNA分子产生tRNA衍生的应激诱导RNA（tiRNAs）触发的。反过来，能够组装G4结构的选择性tiRNAs（G4-tiRNAs）保护运动神经元免受应激诱导的损伤和死亡。这种神经保护是通过G4-tiRNA在转录后水平上重编程基因表达的能力和通过促进应激颗粒（SG）（ALS发病机制中涉及的促存活RNA颗粒）来实现的。值得注意的是，疾病相关的六聚体GGGGCC（G4 C2）重复扩增在C9 ORF 72基因的第一个内含子是最常见的遗传原因额颞叶痴呆（FTD）和肌萎缩侧索硬化症（C9-FTD/ALS）。大量研究表明，具有病理性G4 C2重复序列的C9 ORF 72转录物（称为RNA-G4 C2或rG 4C 2）显著促进C9-FTD/ALS的发生。我们和其他人最近发现，rG 4C 2重复组装G4。我们在这里假设，G4发挥重要的调节作用，这是改变其扩增（如G4 C2扩增过程中观察到的）。了解G-四链体在神经退行性变中的生理作用将为ALS的细胞和分子机制提供重要的见解，并将评估用于治疗运动神经元疾病的新型G4治疗方法。

 DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that currently has no cure. We propose to investigate the roles of G-quadruplex (G4) structures and G4-assembling molecules in neurodegeneration and ALS pathogenesis. G4s are unique structures associated with multiple biological processes including genetic instability, transcriptional and post-transcriptional regulation of gene expression. We have previously identified novel stress response pathway, which is triggered by the ribonuclease angiogenin (ANG) by cleavage of cytoplasmic tRNA molecules to produce tRNA-derived stress-induced RNAs (tiRNAs). In turn, selective tiRNAs that are capable of assembling G4 structures (G4-tiRNAs) protect motor neurons from stress-induced injuries and death. This neuroprotection is achieved by the ability of G4-tiRNAs to reprogram gene expression on post-transcriptional level and by promotion of Stress Granules (SGs), pro- survival RNA granules implicated in the pathogenesis of ALS. Significantly, the disease-associated hexameric GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (C9-FTD/ALS). Number of studies has shown that C9ORF72 transcripts with pathological G4C2 repeats (referred as RNA-G4C2 or rG4C2) significantly contribute to the development of C9-FTD/ALS. We and others have recently discovered that rG4C2 repeats assemble G4s. We hypothesize here that G4s play important regulatory roles, which are altered upon their amplification (such as observed during G4C2 expansion). Understanding of the physiological roles of G-quadruplexes in the context of neurodegeneration will provide important insights into the cellular and molecular mechanisms of ALS, and will evaluate novel G4- based therapeutic approaches for the treatment of motor neuron disease.