Hexanucleotide repeat translation in ALS and Frontotemporal Dementia

ALS 和额颞叶痴呆中的六核苷酸重复翻译

• 批准号: 10680134
• 负责人: Peter K Todd
• 金额: $ 66.54万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680134
• 关键词: Amyotrophic Lateral Sclerosis; Behavior; Biochemical; Biological; Biological Models; C9ORF72; Cells; Cellular Stress; Codon Nucleotides; Complementary DNA; Complex; Data; Dipeptides; Disease; Event; Frontotemporal Dementia; G-Quartets; Genes; Genetic; Genetic Transcription; Goals; Human; In Vitro; Initiator Codon; Introns; Measures; Messenger RNA; Modeling; Nature; Neurons; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Play; Polyribosomes; Positioning Attribute; Process; Production; Proteins; Quality Control; RNA; RNA Helicase; RNA-Binding Proteins; Reading Frames; Repetitive Sequence; Ribosomes; Rodent; Role; Structure; System; Techniques; Transcription Initiation; Translating; Translation Initiation; Translations; Ubiquitin; Work; c9FTD/ALS; frontotemporal lobar dementia amyotrophic lateral sclerosis; in vivo; induced pluripotent stem cell; insight; mRNA capping; multicatalytic endopeptidase complex; neurotoxicity; novel; stem cell model; therapeutic development; therapeutic target

Hexanucleotide repeat translation in ALS and Frontotemporal Dementia The most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD) is an intronic GGGGCC (G4C2) hexanucleotide repeat expansion in the gene C9orf72 (C9FTD/ALS). Despite its position within an intron, the C9orf72 repeat triggers synthesis of dipeptide repeat proteins (DPRs) via a process known as Repeat Associated Non-AUG (RAN) Translation. Studies by our group and others over the past decade have defined key mechanistic parameters that regulate RAN translational initiation and identified selective modulators of RAN translation that suppress disease relevant phenotypes in model systems. In this renewal application, we will address two key questions. 1) What mRNA template(s) are used for C9RAN translation endogenously? Some data suggests that repeat-containing lariats are stabilized and translated. We propose an alternative model where aberrant transcription initiation within the intron itself generates linear 5’ M7G capped mRNA species that robustly support RAN translation. 2) What impact does repeat RNA structure have on C9RAN translational initiation and elongation? Our preliminary studies suggest that both repeat RNA structure dynamics and ribosomal quality control (RQC) pathways act as critical modulators of RAN translation by eliciting ribosomal stalling and altering translational initiation and elongation rates. Our central hypothesis is that GC-rich repeats generate aberrant mRNA species whose RNA structure directly influences their capacity for translation and neurotoxicity. Our goals are to determine the relative contributions of different potential endogenous mRNA species to C9RAN translation and the impact of repeat RNA structure on RAN translational efficiency and RQC engagement. Our central premise is that a detailed understanding of C9RAN translation will both uncover potential therapeutic targets for repeat expansion disorders including C9 FTD/ALS and reveal novel biological insights into aberrant translation events in neurons. In sum, this work will rigorously explore the mechanisms underlying C9 RAN translation, enhance our understanding of protein translational dynamics in neurons and repeat expansion disorder pathogenesis while simultaneously providing a rational path towards therapeutic development in ALS and FTD.

ALS和额颞叶痴呆中的六核苷酸重复翻译 肌萎缩侧索硬化症（ALS）和额颞叶痴呆症最常见的遗传原因 (FTD)是基因C9 orf 72中的内含子GGGGCC（G4 C2）六核苷酸重复扩增 （C9FTD/ALS）。尽管C9 orf 72位于内含子内，但其重复序列触发二肽的合成 重复蛋白（DPR）通过称为重复相关非AUG（RAN）翻译的过程。研究 在过去的十年里，我们的小组和其他人已经定义了调节 RAN翻译起始和经鉴定的抑制疾病的RAN翻译的选择性调节剂 模型系统中的相关表型。 在这次更新申请中，我们将解决两个关键问题。1)mRNA模板用于什么 C9 RAN翻译是内源性的吗？一些数据表明，含重复的拉里是稳定的， は自动的我们提出了一种替代模型，即内含子本身的异常转录起始 产生线性5'M7 G加帽的mRNA种类，其稳健地支持RAN翻译。2)什么影响 重复RNA结构对C9 RAN翻译起始和延伸有影响吗？我们的初步 研究表明，重复RNA结构动力学和核糖体质量控制（RQC）途径 作为RAN翻译的关键调节剂，通过引发核糖体停滞和改变翻译 引发和延伸率。 我们的中心假设是富含GC的重复序列产生了异常的mRNA种类， 直接影响它们的翻译能力和神经毒性。我们的目标是确定 不同潜在内源性mRNA种类对C9 RAN翻译的贡献以及 重复RNA结构对RAN翻译效率和RQC接合的影响。我们的中心前提是， 对C9 RAN翻译的详细了解将揭示重复序列的潜在治疗靶点， 包括C9 FTD/ALS在内的扩增障碍，并揭示了异常翻译的新生物学见解 神经元中的事件。总之，这项工作将严格探索C9 RAN的机制 翻译，增强我们对神经元中蛋白质翻译动力学的理解， 扩张障碍的发病机制，同时提供了合理的途径， ALS和FTD的发展。