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

基本信息

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
项目类别：
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

项目摘要

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和额颞痴呆中的六核苷酸重复翻译肌萎缩性侧索硬化症（ALS）和额颞痴呆的最常见遗传原因（FTD）是基因C9orf72中的内含子GGGGCC（G4C2）六核苷酸重复膨胀（C9FTD/ALS）。尽管在内含子中位置位置，但C9orf72重复触发器的二肽合成通过称为重复相关的非aug（ran）翻译的过程重复蛋白质（DPRS）。研究在过去的十年中，我们的小组和其他人定义了调节的关键机械参数制定了转化计划并确定了抑制疾病的转化的选择性调节剂模型系统中的相关表型。在此续订应用程序中，我们将解决两个关键问题。 1）用于什么mRNA模板用于 C9RAN的内源性翻译？一些数据表明，重复的套索是稳定的，并且翻译。我们提出了一个替代模型，其中内含子内部异常转录启动生成线性5'M7G限制的mRNA物种，可稳健地支持翻译。 2）什么影响重复的RNA结构在C9RAN翻译计划和伸长率上是否具有？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）途径通过引起核糖体失速和改变翻译的转换作为关键调节器启动和伸长率。我们的中心假设是，富含GC的重复会产生异常的mRNA物种，其RNA结构直接影响其翻译和神经毒性的能力。我们的目标是确定亲戚不同潜在的内源mRNA物种对C9RAN翻译的贡献以及重复RNA结构在RAN转化效率和RQC参与度上。我们的中心前提是对C9RAN翻译的详细理解都将发现重复的潜在治疗靶标包括C9 FTD/ALS在内的扩张障碍，并揭示了对异常翻译的新型生物学见解神经元中的事件。总而言之，这项工作将严格探索C9的基础机制翻译，增强我们对神经元中蛋白质翻译动力学的理解并重复扩张障碍发病机理，同时提供治疗的合理途径 ALS和FTD的开发。