DDX3X overexpression decreases dipeptide repeat proteins in a mouse model of C9ORF72-ALS/FTD.
DDX3X overexpression decreases dipeptide repeat proteins in a mouse model of C9ORF72-ALS/FTD.
复制标题
DDX3X 过表达会减少 C9ORF72-ALS/FTD 小鼠模型中的二肽重复蛋白。
DOI：
10.1016/j.expneurol.2024.114768
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发表时间：
2024
影响因子：
5.3
通讯作者：
Sun,Shuying
中科院分区：
文献类型：
--
作者：
Fu,Xiujuan;Zhang,Zhe;Hayes,LindseyR;Wright,Noelle;Asbury,Julie;Li,Shelley;Ye,Yingzhi;Sun,Shuying
C9 ORF 72（C9）中的六核苷酸重复扩增是肌萎缩侧索硬化（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由重复相关非AUG（RAN）翻译产生的二肽重复（DPR）蛋白引起的神经毒性。因此，降低DPR水平成为C9 ORF 72-ALS/FTD的潜在治疗策略。我们以前确定了RNA解旋酶，DEAD盒解旋酶3 X-连锁（DDX 3X），调节RAN翻译。DDX 3X过表达减少了C9 ORF 72-ALS/FTD患者来源的诱导多能干细胞（iPSC）分化神经元（iPSN）中的聚GP积累，并减少了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测DDX 3X过表达的体内功效。我们使用腺相关病毒血清型9（AAV 9）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）中表达外源性DDX 3X或GFP。即使在病毒递送后12个月，与GFP对照相比，表达DDX 3X的C9-BAC小鼠的脑中的DPR水平也显著降低。此外，p62聚集也减少。在DDX 3X过表达C9-BAC小鼠中未检测到神经元损失或神经炎症反应。这项工作表明，DDX 3X过表达可有效降低体内DPR水平，而不会引起神经炎症或神经毒性，表明增加DDX 3X表达作为C9 ORF 72-ALS/FTD治疗策略的潜力。
Hexanucleotide repeat expansion inC9ORF72(C9) 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 thein vivoefficacy 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 levelsin vivowithout provoking neuroinflammation or neurotoxicity, suggesting the potential of increasing DDX3X expression as a therapeutic strategy for C9ORF72-ALS/FTD.