Expansion of intronic GGGGCC repeats in the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Transcription of the expanded repeats results in the formation of RNA-containing nuclear foci and altered RNA metabolism. In addition, repeat-associated non-AUG (RAN) translation of the expanded GGGGCC-repeat sequence results in the production of highly toxic dipeptide-repeat (DPR) proteins. GGGGCC repeat–containing transcripts form G-quadruplexes, which are associated with formation of RNA foci and RAN translation. Zfp106, an RNA-binding protein essential for motor neuron survival in mice, suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Here, we show that Zfp106 inhibits formation of RNA foci and significantly reduces RAN translation caused by GGGGCC repeats in cultured mammalian cells, and we demonstrate that Zfp106 coexpression reduces the levels of DPRs in C9orf72 patient-derived cells. Further, we show that Zfp106 binds to RNA G-quadruplexes and causes a conformational change in the G-quadruplex structure formed by GGGGCC repeats. Together, these data demonstrate that Zfp106 suppresses the formation of RNA foci and DPRs caused by GGGGCC repeats and suggest that the G-quadruplex RNA-binding function of Zfp106 contributes to its suppression of GGGGCC repeat-mediated cytotoxicity.

中文翻译：

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Zfp106 与 G 四链体 RNA 结合并抑制 RAN 翻译和由 G4C2 重复引起的 RNA 焦点的形成


C9orf72 基因中内含子 GGGGCC 重复序列的扩展会导致肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆。扩展的重复序列的转录导致含有RNA的核灶的形成并改变RNA代谢。此外，扩展的 GGGGCC 重复序列的重复相关非 AUG (RAN) 翻译会导致产生剧毒的二肽重复 (DPR) 蛋白。含有 GGGGCC 重复序列的转录物形成 G 四链体，与 RNA 焦点的形成和 RAN 翻译相关。 Zfp106 是一种对小鼠运动神经元存活至关重要的 RNA 结合蛋白，可抑制 C9orf72 ALS 果蝇模型中的神经毒性。在这里，我们证明 Zfp106 抑制 RNA 焦点的形成，并显着减少培养的哺乳动物细胞中由 GGGGCC 重复引起的 RAN 翻译，并且我们证明 Zfp106 共表达降低了 C9orf72 患者来源的细胞中的 DPR 水平。此外，我们还发现 Zfp106 与 RNA G 四链体结合，并引起 GGGGCC 重复形成的 G 四链体结构的构象变化。总之，这些数据表明 Zfp106 抑制由 GGGGCC 重复引起的 RNA 焦点和 DPR 的形成，并表明 Zfp106 的 G 四链体 RNA 结合功能有助于其抑制 GGGGCC 重复介导的细胞毒性。