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

基本信息

批准号：
10553169
负责人：
Peter K Todd
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
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/10553169
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 Cytoplasm DNA Data Dipeptides Disease Double-Stranded RNA EIF-2alpha 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 Peptide Initiation Factors 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 biological adaptation to stress c9FTD/ALS 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

项目摘要

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）的最常见遗传原因是六核苷酸（G4C2）六核苷酸的链球植物疗法的增长量是基因C9orf72的扩张（C9 FTD/ALS）。至少在二型二肽重复蛋白的二肽中启动（RAS）的一部分。（P-EIF2α），损害启动型tRNA（TRNAIMET）掺入前的蛋白质合成中，并触发压力颗粒的形成，相反，P-EIF2α通过选择性增强了C9，从而有利于使用非aug start Codon和Ireslated的使用。此外，G4C2重复触发应力颗粒，并通过相同的途径损害全局的蛋白质翻译。循环是对细胞TRESS的反应的静脉Toxity和Alter TDP-43我们的长期是在C9 FTD/ALS和其他神经退行性疾病中定义强大的治疗靶标。