A GGGGCC hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense repeat-containing transcripts undergo repeat-associated non-AUG-initiated translation to produce five dipeptide proteins (DPRs). The polyGR and polyPR DPRs are extremely toxic when expressed in Drosophila neurons. To determine the mechanism that mediates this toxicity, we purified DPRs from the Drosophila brain and used mass spectrometry to identify the in vivo neuronal DPR interactome. PolyGR and polyPR interact with ribosomal proteins, and inhibit translation in both human iPSC-derived motor neurons, and adult Drosophila neurons. We next performed a screen of 81 translation-associated proteins in GGGGCC repeat-expressing Drosophila to determine whether this translational repression can be overcome and if this impacts neurodegeneration. Expression of the translation initiation factor eIF1A uniquely rescued DPR-induced toxicity in vivo, indicating that restoring translation is a potential therapeutic strategy. These data directly implicate translational repression in C9orf72 repeat-induced neurodegeneration and identify eIF1A as a novel modifier of C9orf72 repeat toxicity.

中文翻译：

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C9orf72 富含精氨酸的二肽蛋白在体内与核糖体蛋白相互作用，诱导由 eIF1A 拯救的有毒翻译停滞。

C9orf72 基因内的 GGGGCC 六核苷酸重复扩增是肌萎缩侧索硬化和额颞叶痴呆最常见的遗传原因。包含有义和反义重复的转录物经历重复相关的非 AUG 起始的翻译以产生五种二肽蛋白 (DPR)。polyGR 和 polyPR DPR 在果蝇神经元中表达时具有剧毒。为了确定介导这种毒性的机制，我们从果蝇大脑中纯化了 DPR，并使用质谱法来鉴定体内神经元 DPR 相互作用组。PolyGR 和 polyPR 与核糖体蛋白相互作用，并抑制人类 iPSC 衍生的运动神经元和成年果蝇神经元的翻译。接下来，我们对 GGGGCC 重复表达果蝇中的 81 种翻译相关蛋白进行了筛选，以确定是否可以克服这种翻译抑制以及这是否会影响神经变性。翻译起始因子 eIF1A 的表达独特地挽救了 DPR 诱导的体内毒性，表明恢复翻译是一种潜在的治疗策略。这些数据直接暗示 C9orf72 重复诱导的神经变性中的翻译抑制，并将 eIF1A 鉴定为 C9orf72 重复毒性的新修饰剂。