C9ORF72-derived dipeptide repeat proteins have emerged as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms underlying their expression are not fully understood. Here, we demonstrate that ZNF598, the rate-limiting factor for ribosome-associated quality control (RQC), co-translationally titrates the expression of C9ORF72-derived poly(GR) protein. A Drosophila genetic screen identified key RQC factors as potent modifiers of poly(GR)-induced neurodegeneration. ZNF598 overexpression in human neuroblastoma cells inhibited the nuclear accumulation of poly(GR) protein and decreased its cytotoxicity, whereas ZNF598 deletion had opposing effects. Poly(GR)-encoding sequences in the reporter RNAs caused translational stalling and generated ribosome-associated translation products, sharing molecular signatures with canonical RQC substrates. Furthermore, ZNF598 and listerin 1, the RQC E3 ubiquitin-protein ligase, promoted poly(GR) degradation via the ubiquitin-proteasome pathway. An ALS-relevant ZNF598R69C mutant displayed loss-of-function effects on poly(GR) expression, as well as on general RQC. Moreover, RQC function was impaired in C9-ALS patient-derived neurons, whereas lentiviral overexpression of ZNF598 lowered their poly(GR) expression and suppressed proapoptotic caspase-3 activation. Taken together, we propose that an adaptive nature of the RQC-relevant ZNF598 activity allows the co-translational surveillance to cope with the atypical expression of pathogenic poly(GR) protein, thereby acquiring a neuroprotective function in C9-ALS/FTD.

中文翻译：

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ZNF598 共翻译滴定与 C9ORF72 相关 ALS/FTD 发病机制有关的多 (GR) 蛋白

C9ORF72 衍生的二肽重复蛋白已成为肌萎缩侧索硬化症和额颞叶痴呆 (C9-ALS/FTD) 中神经变性的致病原因。然而，它们表达的机制尚不完全清楚。在这里，我们证明了 ZNF598，核糖体相关质量控制 (RQC) 的限速因子，共翻译滴定 C9ORF72 衍生的聚 (GR) 蛋白的表达。果蝇基因筛选确定关键的 RQC 因素是 poly(GR) 诱导的神经变性的有效调节剂。ZNF598 在人神经母细胞瘤细胞中的过度表达抑制了聚 (GR) 蛋白的核积累并降低了其细胞毒性，而 ZNF598 缺失具有相反的作用。报告 RNA 中的多 (GR) 编码序列导致翻译停滞并产生与核糖体相关的翻译产物，与典型的 RQC 底物共享分子特征。此外，ZNF598 和李斯特林 1（RQC E3 泛素-蛋白连接酶）通过泛素-蛋白酶体途径促进 poly(GR) 降解。与 ALS 相关的 ZNF598R69C 突变体显示出对 poly(GR) 表达以及一般 RQC 的功能丧失影响。此外，C9-ALS 患者衍生的神经元中的 RQC 功能受损，而 ZNF598 的慢病毒过表达降低了它们的 poly(GR) 表达并抑制了促凋亡 caspase-3 的激活。总之，我们提出 RQC 相关 ZNF598 活性的适应性特性允许共翻译监视以应对致病性多 (GR) 蛋白的非典型表达，