The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA1 interacts with TRIM21, and α-GA1 treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA1 reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA1 is important for cell entry and efficacy. These data demonstrate that RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.

中文翻译：

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靶向 RAN 蛋白的抗体治疗可挽救 C9orf72 小鼠模型中的 C9 ALS/FTD 表型。

内含子 C9orf72 G4C2 扩增是 ALS 和 FTD 最常见的遗传原因，产生正义和反义扩增 RNA 和六种二肽重复相关的非 ATG (RAN) 蛋白，但它们在疾病中的作用尚不清楚。我们生成了针对 GA 或 GP RAN 蛋白的高亲和力人类抗体。这些抗体穿过血脑屏障并与 C9-ALS/FTD BAC 小鼠的细胞内 RAN 聚集体共定位。在细胞中，α-GA1 与 TRIM21 相互作用，α-GA1 处理降低了 GA 水平，增加了 GA 周转率，降低了 RAN 毒性以及蛋白酶体和自噬蛋白与 GA 聚集体的共聚集。在 C9-BAC 小鼠中，α-GA1 减少了 GA 以及 GP 和 GR 蛋白，改善了行为缺陷，减少了神经炎症和神经变性，并提高了存活率。α-GA1 Fc 区的糖基化对细胞进入和功效很重要。这些数据表明 RAN 蛋白在 C9-BAC 转基因小鼠中驱动 C9-ALS/FTD，并为 C9orf72 ALS/FTD 和其他 RAN 蛋白疾病建立了一种新的治疗方法。