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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：
9920791
负责人：
Peter K Todd
金额：
$ 45.45万
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 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920791
关键词：
ALS patients Amyotrophic Lateral Sclerosis Base Sequence Biochemical Biological Assay Biological Models Bypass C9ORF72 CGG repeat Cell Culture Techniques Cells Cessation of life Collection Complex Dipeptides Disease Drosophila genus FMR1 FXTAS Family Fragile X Gene Genes Genetic Genetic Transcription Genome Impairment In Vitro Initiator Codon Introns Lead Maps Mediating Messenger RNA Methods Modeling Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nucleotides Pathogenesis Pathway interactions Patients Peptide Initiation Factors Peptides Positioning Attribute Prevalence Process Proteins RNA RNA Helicase RNA Sequences RNA Splicing RNA interference screen Reading Frames Recording of previous events Reporter Ribosomes Rodent Role Scanning Series System Techniques Testing Therapeutic Toxic effect Transcript Translating Translation Initiation Translations Work base c9FTD/ALS disability effective therapy fly frontotemporal lobar dementia-amyotrophic lateral sclerosis helicase induced pluripotent stem cell inhibitor/antagonist mutant novel novel therapeutics overexpression polyglycine polysome profiling prevent recruit small molecule therapeutics stem cell model therapeutic development tool transcriptome unpublished works viral RNA

项目摘要

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD) are common neurodegenerative disorders that are progressive, fatal, and without effective treatment. Recently, the most common known cause of ALS and FTD was identified as an intronic GGGGCC hexanucleotide repeat expansion in the gene C9orf72 (C9FTD/ALS). This repeat triggers synthesis of toxic proteins via a process known as Repeat Associated Non-AUG (RAN) Translation. These RAN peptides kill neurons and are sufficient to cause neurodegeneration in model systems. We know very little about how RAN translation at C9 repeats (C9 RANT) actually occurs. The objective of this proposal is to determine the mechanisms underlying C9 RAN and to identify methods of blocking it as a first step towards novel therapeutic development. Our central hypothesis is that C9 RAN utilizes a non-canonical translational initiation pathway that can be selectively blocked. Moreover, we predict that preventing C9 RAN will stop neurodegeneration elicited by GGGGCC repeats. To test these hypotheses, we developed robust and quantitative in vitro and cell based assays of C9 RANT, as well as a collection of models derived from patient induced pluripotent stem cells, rodent neurons, and Drosophila. Using these tools, we will define the mRNA species that undergo C9 RANT, identify the critical RNA and protein based factors that allow for C9 RANT and test whether suppressing C9 RANT by modulating the surrounding sequence or protein factors can block toxicity in model systems. Together, these studies should provide us with a working map of how C9 RAN occurs and what steps can be taken to prevent it. This project has broad reaching implications both for our understanding of how RAN translation contributes to disease as well as providing a logical path towards therapeutic development in C9FTD/ALS and other neurodegenerative nucleotide repeat disorders.

肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 是常见的神经退行性疾病进行性、致命性且无法有效治疗的疾病。最近最常见的就是 ALS 和 FTD 的病因被确定为基因中的内含子 GGGGCC 六核苷酸重复扩增 C9orf72 (C9FTD/ALS)。这种重复通过称为重复的过程触发有毒蛋白质的合成关联的非 AUG (RAN) 翻译。这些 RAN 肽杀死神经元并足以引起模型系统中的神经变性。我们对 C9 处的 RAN 翻译如何重复（C9 RANT）确实发生了。该提案的目标是确定 C9 RAN 的底层机制确定阻断它的方法，作为开发新疗法的第一步。我们的中心假设 C9 RAN 利用了一种可以选择性阻断的非规范翻译起始途径。此外，我们预测阻止 C9 RAN 将阻止 GGGGCC 重复引起的神经变性。到为了测试这些假设，我们开发了 C9 RANT 的稳健且定量的体外和基于细胞的测定法，如以及源自患者诱导多能干细胞、啮齿动物神经元和果蝇。使用这些工具，我们将定义经历 C9 RANT 的 mRNA 种类，识别关键的基于 RNA 和蛋白质的因子，允许 C9 RANT 并测试是否通过调节抑制 C9 RANT 周围的序列或蛋白质因子可以阻止模型系统中的毒性。这些研究共同应该为我们提供一份工作图，说明 C9 RAN 如何发生以及可以采取哪些步骤来防止它发生。这该项目对于我们理解 RAN 翻译如何做出贡献具有广泛的影响疾病以及为 C9FTD/ALS 和其他疾病的治疗开发提供逻辑路径神经退行性核苷酸重复障碍。