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: 9890664
• 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/9890664
• 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; 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 额颞叶痴呆 (FTD) 和肌萎缩侧索硬化症 (ALS) 最常见的遗传原因是 C9orf72 (C9 FTD/ALS) 基因中的内含子 GGGGCC (G4C2) 六核苷酸重复扩增。这种重复可能至少部分通过重复相关的非 AUG 起始 (RAN) 翻译将重复序列翻译成二肽重复蛋白而引起神经变性。我们自己的小组研究了 C9orf72 重复序列 (C9 RAN) 的 RAN 翻译机制。这项工作表明 C9 RAN 对细胞应激途径的变化非常敏感。在综合应激反应过程中，蛋白质稳态受损和病毒感染等损伤会触发起始因子 eIF2α 磷酸化 (p-eIF2α)，从而损害起始因子 tRNA (tRNAiMet) 掺入起始前复合物，阻碍整体蛋白质合成并触发应激颗粒形成。相比之下，p-eIF2α 通过选择性地支持使用非 AUG 起始密码子和 IRES 介导的翻译来增强 C9 RAN。此外，G4C2 重复会触发应激颗粒的形成，并通过同一途径损害整体蛋白质翻译。细胞应激途径、应激颗粒形成、核苷酸重复和神经变性之间的功能相互作用尚不清楚，但可能是 ALS 和 FTD 病理生理学的核心。我们的初步数据表明，C9 RAN 和细胞应激通路参与能够导致神经退行性变的前馈循环。因此，介导这种恶性循环的途径是潜在的治疗靶点。我们的中心假设是，C9 RAN 响应细胞应激的异常激活会导致 C9 FTD/ALS 中的神经变性。我们的目标是确定细胞应激途径如何激活 RAN 翻译，G4C2 重复如何激活和维持细胞应激，确定 SG 形成是否是重复引起的神经变性的核心，并评估选择性细胞应激途径或 RAN 翻译的抑制是否减轻 G4C2 重复毒性并改变 TDP-43 病理学。我们的长期目标是确定 C9 FTD/ALS 和其他神经退行性疾病的稳健治疗靶点。