Bypassing cellular stress pathways in frontotemporal dementia and ALS

绕过额颞叶痴呆和 ALS 的细胞应激途径

• 批准号: 10438531
• 负责人: Peter K Todd
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438531
• 关键词: ALS patients; Affect; Amyotrophic Lateral Sclerosis; Biochemical; Biological Models; Biology; Bypass; C9ORF72; Cell Line; Cellular Stress; Cessation of life; Chronic stress; Complex; DNA; Data; Dipeptides; Disease; Double-Stranded RNA; Eukaryotic Initiation Factor-2; Excision; Functional disorder; Genes; Genetic; Goals; Human; Impairment; Induced pluripotent stem cell derived neurons; Initiator Codon; Initiator tRNA; Internal Ribosome Entry Site; Knock-out; Lead; Link; Measures; Mediating; Messenger RNA; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nucleotides; PRKR gene; Pathogenesis; Pathology; Pathway interactions; Patients; Peat; Peptide Initiation Factors; Peptides; Phenotype; Phosphorylation; Phosphotransferases; Process; Protein Biosynthesis; Proteins; RNA; Recycling; Repetitive Sequence; Reporter; Ribosomes; Rodent; Scanning; Series; Stress; System; Techniques; Testing; Therapeutic; Toxic effect; Translating; Translation Initiation; Translations; Veterans; Virus Diseases; Work; age related neurodegeneration; base; biological adaptation to stress; disability; eukaryotic initiation factor-5B; frontotemporal lobar dementia-amyotrophic lateral sclerosis; induced pluripotent stem cell; insight; knock-down; mouse model; prevent; protein TDP-43; protein function; proteostasis; response; stem cell model; stress granule; stress state; therapeutic target

Cell stress pathways in ALS The most common genetic cause of both Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) is an intronic GGGGCC (G4C2) hexanucleotide repeat expansion in the gene C9orf72 (C9 FTD/ALS). This repeat likely elicits neurodegeneration at least in part through repeat associated non AUG initiated (RAN) translation of the repeats into dipeptide repeat proteins. Our own group has studied the mechanisms underlying RAN translation at C9orf72 repeats (C9 RAN). This work reveals that C9 RAN is very sensitive to alterations in cellular stress pathways. During the integrated stress response, insults such as impaired proteostasis and viral infections trigger initiation factor eIF2α phosphorylation (p-eIF2α), which impairs initiator tRNA (tRNAiMet) incorporation into pre-initiation complexes, blocks global protein synthesis and triggers stress granule formation. In contrast, p-eIF2α enhances C9 RAN by selectively favoring the use of non-AUG start codons and IRES mediated translation. Moreover, G4C2 repeats trigger Stress granule formation and impair global protein translation through this same pathway. The functional interplay between cellular stress pathways, stress granule formation, nucleotide repeats, and neurodegeration are poorly understood but potentially central to the pathophysiology of ALS and FTD. Our preliminary data suggests that C9 RAN and cellular stress pathways participate in a feed-forward loop capable of causing neurodegeneration. The pathways that mediate this vicious cycle are thus potential therapeutic targets. Our central hypothesis is that aberrant activation of C9 RAN in response to cellular stress drives neurodegeneration in C9 FTD/ALS. Our goals are to determine how cellular stress pathways activate RAN translation, how G4C2 repeats activate and maintain cellular stress, define whether SG formation is central to repeat elicited neurodegeneration, and evaluate whether inhibition of selective cellular stress pathways or RAN translation alleviate G4C2 repeat toxicity and alter TDP-43 pathology. Our long-term objective is to define robust therapeutic targets in C9 FTD/ALS and other neurodegenerative disorders.

ALS中的细胞应激途径是额颞痴呆（FTD）和肌萎缩性侧面硬化症（ALS）最常见的遗传原因是内含子GGGGCC（G4C2）六核苷酸的重复替代基因C9orf72（C9 FTD/ALS）。这种重复可能至少通过重复相关的非AUM启动（RAN）翻译到二肽重复蛋白中的重复非AUG（RAN）转换至少会引起神经变性。我们自己的小组研究了C9orf72重复序列（C9 RAN）的基础机制。这项工作表明，C9 RAN对细胞应力途径的改变非常敏感。在整合应激反应中，诸如损伤的蛋白质和病毒感染损害触发了启动因子EIF2α磷酸化因子（P-EIF2α），损害了引发剂tRNA（TRNAIMET）掺入的引发剂tRNA（TRNAIMET）中，纳入了入生成络合物中，阻止了全球蛋白质合成和触发压力颗粒状的形成。相比之下，P-EIF2α通过选择性地使用非aug启动密码子和IRES介导的翻译来增强C9的运行。此外，G4C2重复触发应力颗粒的形成，并通过相同的途径损害了全局蛋白质的翻译。细胞应激途径，应力颗粒的形成，核苷酸重复和神经变性之间的功能相互作用知之甚少，但可能与ALS和FTD的病理生理学有关。我们的初步数据表明，C9运行，细胞应力途径参与了能够引起神经变性的馈送环路。因此，介导这种恶性循环的途径是潜在的治疗靶标。我们的中心假设是，C9的异常激活响应细胞应激驱动C9 FTD/ALS的神经退行性。我们的目标是确定细胞应力途径如何激活RAN翻译，G4C2如何重复激活和维持细胞应力，定义SG形成是重复引起神经变性的核心，并评估抑制选择性细胞应力途径还是抑制转化的G4C2重复毒性和改变TDP-43病理学。我们的长期目标是定义C9 FTD/ALS和其他神经退行性疾病中的鲁棒治疗靶标。