Lin Chun-Yu, Wu Hsuan-Cheng, Fu Ru-Huei, Weng Eddie Feng-Ju, Hsieh Wen-Chi, Su Tsung-Ping, Wu Hsiang-En, Wang Shao-Ming
Neuroscience and Brain Disease Center, China Medical University, Taichung 404328, Taiwan; School of Medicine, College of Medicine, China Medical University, Taichung 404328, Taiwan.
Neuroscience and Brain Disease Center, China Medical University, Taichung 404328, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404328, Taiwan.
Neurobiol Dis. 2025 Aug;212:106992. doi: 10.1016/j.nbd.2025.106992. Epub 2025 Jun 5.
Nucleocytoplasmic transport disruption contributes to the pathogenesis of C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Among the dipeptide repeat proteins translated from G4C2-repeat RNA, poly-PR is particularly toxic, compromising nuclear envelope integrity and transport. Here, we revealed that poly-PR reduced expression of the nucleoporin Pom121 in NSC-34 cells and in an AAV-mediated poly-PR mouse model, resulting in cytoplasmic mislocalization of the neuroprotective transcription factor ATF3 and nuclear envelope damage. Pom121 overexpression restored nuclear ATF3 localization and alleviated poly-PR-induced toxicity. We further identified Sigma-1 receptor (Sigma-1R) as a stabilizer of Pom121 that preserved nuclear integrity and ATF3 function under oxidative stress. Overexpression of Sigma-1R, Pom121, or ATF3 rescued poly-PR-induced cytotoxicity. Our findings defined a protective Sigma-1R/Pom121/ATF3 axis and suggested this pathway as a therapeutic target in C9orf72-linked ALS.
核质运输破坏参与了与C9orf72相关的肌萎缩侧索硬化症（ALS）和额颞叶痴呆的发病机制。在从G4C2重复RNA翻译而来的二肽重复蛋白中，聚脯氨酸-精氨酸（poly-PR）具有特别强的毒性，会损害核膜完整性和运输功能。在这里，我们发现poly-PR降低了NSC-34细胞和AAV介导的poly-PR小鼠模型中核孔蛋白Pom121的表达，导致神经保护转录因子ATF3在细胞质中定位错误以及核膜损伤。Pom121的过表达恢复了ATF3在细胞核中的定位，并减轻了poly-PR诱导的毒性。我们进一步确定西格玛-1受体（Sigma-1R）是Pom121的稳定剂，在氧化应激下可维持核完整性和ATF3功能。Sigma-1R、Pom121或ATF3的过表达可挽救poly-PR诱导的细胞毒性。我们的研究结果确定了一条保护性的Sigma-1R/Pom121/ATF3轴，并表明该途径可作为C9orf72相关ALS的治疗靶点。
