Bypassing cellular stress pathways in frontotemporal dementia and ALS

额颞叶痴呆（FTD）和肌萎缩侧索硬化（ALS）最常见的遗传原因是基因C9 orf 72（C9 FTD/ALS）中的内含子GGGGCC（G4 C2）六核苷酸重复扩增。这种重复可能至少部分地通过重复相关的非AUG起始（RAN）的重复翻译成二肽重复蛋白来促进神经变性。我们自己的小组研究了C9 orf 72重复序列（C9 RAN）的RAN翻译机制。这项工作表明，C9 RAN对细胞应激途径的改变非常敏感。在整合应激反应期间，蛋白质稳态受损和病毒感染等损伤触发起始因子eIF 2 α磷酸化（p-eIF 2 α），其损害起始tRNA（tRNAiMet）掺入前起始复合物，阻断整体蛋白质合成并触发应激颗粒形成。相比之下，p-eIF 2 α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，G4 C2重复序列触发应激颗粒形成，并通过相同的途径损害整体蛋白质翻译。细胞应激途径、应激颗粒形成、核苷酸重复序列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和细胞应激途径参与能够引起神经退行性变的前馈回路。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驱动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，G4 C2重复序列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G4 C2重复序列毒性并改变TDP-43病理。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。

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.