Hexanucleotide repeat expansion in () is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One of the proposed pathogenic mechanisms is the neurotoxicity arising from dipeptide repeat (DPR) proteins produced by repeat-associated non-AUG (RAN) translation. Therefore, reducing DPR levels emerges as a potential therapeutic strategy for C9ORF72-ALS/FTD. We previously identified an RNA helicase, DEAD-box helicase 3 X-linked (DDX3X), modulates RAN translation. DDX3X overexpression decreases poly-GP accumulation in C9ORF72-ALS/FTD patient-derived induced pluripotent stem cell (iPSC)-differentiated neurons (iPSNs) and reduces the glutamate-induced neurotoxicity. In this study, we examined the efficacy of DDX3X overexpression using a mouse model. We expressed exogenous DDX3X or GFP in the central nervous system (CNS) of the C9–500 ALS/FTD BAC transgenic or non-transgenic control mice using adeno-associated virus serotype 9 (AAV9). The DPR levels were significantly reduced in the brains of DDX3X-expressing C9-BAC mice compared to the GFP control even twelve months after virus delivery. Additionally, p62 aggregation was also decreased. No neuronal loss or neuroinflammatory response were detected in the DDX3X overexpressing C9-BAC mice. This work demonstrates that DDX3X overexpression effectively reduces DPR levels without provoking neuroinflammation or neurotoxicity, suggesting the potential of increasing DDX3X expression as a therapeutic strategy for C9ORF72ALS/FTD.

中文翻译：

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DDX3X 过表达减少 C9ORF72-ALS/FTD 小鼠模型中的二肽重复蛋白

() 中的六核苷酸重复扩增是肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 最常见的遗传原因。提出的致病机制之一是重复相关的非 AUG (RAN) 翻译产生的二肽重复 (DPR) 蛋白产生的神经毒性。因此，降低 DPR 水平成为 C9ORF72-ALS/FTD 的潜在治疗策略。我们之前鉴定了一种 RNA 解旋酶，DEAD-box 解旋酶 3 X-linked (DDX3X)，可调节 RAN 翻译。 DDX3X 过表达可减少 C9ORF72-ALS/FTD 患者来源的诱导多能干细胞 (iPSC) 分化神经元 (iPSN) 中多聚 GP 的积累，并减少谷氨酸诱导的神经毒性。在这项研究中，我们使用小鼠模型检查了 DDX3X 过度表达的功效。我们使用腺相关病毒血清型 9 (AAV9) 在 C9-500 ALS/FTD BAC 转基因或非转基因对照小鼠的中枢神经系统 (CNS) 中表达外源 DDX3X 或 GFP。即使在病毒递送后 12 个月，与 GFP 对照小鼠相比，表达 DDX3X 的 C9-BAC 小鼠大脑中的 DPR 水平也显着降低。此外，p62 聚集也减少。在 DDX3X 过表达 C9-BAC 小鼠中未检测到神经元丢失或神经炎症反应。这项工作表明，DDX3X 过表达可有效降低 DPR 水平，而不会引发神经炎症或神经毒性，这表明增加 DDX3X 表达作为 C9ORF72ALS/FTD 治疗策略的潜力。