PDF(Pubmed)
Abstract：
Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer\'s disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G4C2)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G4C2)31-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G4C2)31-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G4C2)31-RNA-expressing NSC34 cells.
摘要：
GGGGCC-RNA重复序列的扩增是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的已知原因，目前还没有治愈方法。最近的研究表明，Sigma-1受体的激活在提供神经保护中起着重要作用。特别是在ALS和阿尔茨海默病中。然而，Sigma-1R激活的潜在机制及其对(G4C2)n-RNA诱导的细胞死亡的影响尚不清楚.在这项研究中,我们证明氟伏沙明是一种Sigma-1R激动剂，可以增加伴侣活性并稳定Pom121在（G4C2）31-RNA表达的NSC34细胞中的蛋白表达，导致核膜的共定位增加。有趣的是,氟伏沙明处理增加Pom121蛋白表达而不影响转录。在C9orf72-ALS,由于核质转运缺陷，TFEB自噬因子的核易位减少。我们的结果表明，与单独的（G4C2）31-RNA过表达相比，用氟伏沙明预处理NSC34细胞可促进TFEB穿梭进入细胞核并提高LC3-II的表达。此外,即使单独使用，氟伏沙明增加Pom121表达和TFEB易位。总结一下,氟伏沙明可能是C9orf72-ALS患者的一种有希望的药物，因为它稳定核孔蛋白Pom121并促进TFEB在（G4C2）31-RNA表达NSC34细胞中的易位。
