G-quadruplex Structures as Targets and Tools in ALS

 描述(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，目前尚无治愈方法。我们建议研究G-四链(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。G4S是与多种生物学过程相关的独特结构，包括基因表达的遗传不稳定、转录和转录后调控。我们已经发现了新的应激反应途径，它是由核糖核酸酶血管生成素(Ang)通过裂解细胞质tRNA分子产生tRNA衍生的应激诱导RNAs(TiRNAs)来触发的。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-tiRNAs在转录后水平上重新编程基因表达的能力以及通过促进应激颗粒(SGS)实现的，SGS是与ALS的发病机制有关的有利于生存的RNA颗粒。值得注意的是，C9ORF72基因第一内含子中疾病相关的六聚体GGGGCC(G4C2)重复扩增是导致额颞部痴呆(FTD)和肌萎缩侧索硬化症(C9-FTD/ALS)的最常见的遗传原因。大量研究表明，带有病理性G4C2重复序列的C9ORF72转录本(称为RNA-G4C2或rG4C2)在C9-FTD/ALS的发生发展中具有重要作用。我们和其他人最近发现，rG4C2重复组装G4S。我们假设G4S发挥着重要的调节作用，这种作用会随着它们的扩增而改变(例如在G4C2扩增过程中观察到的)。了解G-四联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，并将评估基于G4的治疗运动神经元病的新方法。

 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.