Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI, USA.
Hum Mol Genet. 2022 Aug 17;31(15):2521-2534. doi: 10.1093/hmg/ddac021.
Repeat-associated non-AUG (RAN) translation of expanded repeat-mutation mRNA produces toxic peptides in neurons of patients suffering from neurodegenerative diseases. Recent findings indicate that RAN translation in diverse model systems is not inhibited by cellular stressors that impair global translation through phosphorylation of the alpha subunit of eIF2, the essential eukaryotic translation initiation factor that brings the initiator tRNA to the 40S ribosome. Using in vitro, cell-based and Drosophila models, we examined the role of alternative ternary complex factors that may function in place of eIF2, including eIF2A, eIF2D, DENR and MCTS1. Among these factors, DENR knockdown had the greatest inhibitory effect on RAN translation of expanded GGGGCC and CGG repeat reporters and its reduction improved the survival of Drosophila expressing expanded GGGGCC repeats. Taken together, these data support a role for alternative initiation factors in RAN translation and suggest these may serve as novel therapeutic targets in neurodegenerative disease.
重复相关的非 AUG（RAN）翻译扩展重复突变 mRNA 在患有神经退行性疾病的神经元中产生毒性肽。最近的研究结果表明，RAN 翻译在不同的模型系统中不受通过磷酸化 eIF2 的 α 亚基来破坏全球翻译的细胞应激物的抑制，eIF2 是将起始 tRNA 带到 40S 核糖体的必需真核翻译起始因子。我们使用体外、基于细胞和果蝇模型，研究了可能替代 eIF2 发挥作用的替代三元复合物因子的作用，包括 eIF2A、eIF2D、DENR 和 MCTS1。在这些因子中，DENR 的敲低对扩展 GGGGCC 和 CGG 重复报告基因的 RAN 翻译具有最大的抑制作用，其减少改善了表达扩展 GGGGCC 重复的果蝇的生存能力。总之，这些数据支持替代起始因子在 RAN 翻译中的作用，并表明它们可能成为神经退行性疾病的新型治疗靶点。
