Repeat associated non-AUG (RAN) translation is found in a growing number of microsatellite expansion diseases, but the mechanisms remain unclear. We show that RAN translation is highly regulated by the double-stranded RNA-dependent protein kinase (PKR). In cells, structured CAG, CCUG, CAGG, and G₄C₂ expansion RNAs activate PKR, which leads to increased levels of multiple RAN proteins. Blocking PKR using PKR-K296R, the TAR RNA binding protein or PKR-KO cells, reduces RAN protein levels. p-PKR is elevated in C9orf72 ALS/FTD human and mouse brains, and inhibiting PKR in C9orf72 BAC transgenic mice using AAV-PKR-K296R or the Food and Drug Administration (FDA)-approved drug metformin, decreases RAN proteins, and improves behavior and pathology. In summary, targeting PKR, including by use of metformin, is a promising therapeutic approach for C9orf72 ALS/FTD and other expansion diseases.

在越来越多的微卫星扩张疾病中发现了重复相关的非 AUG (RAN) 翻译，但其机制尚不清楚。我们表明 RAN 翻译受到双链 RNA 依赖性蛋白激酶 (PKR) 的高度调节。在细胞中，结构化 CAG、CCUG、CAGG 和 G ₄ C ₂扩增 RNA 会激活 PKR，从而导致多种 RAN 蛋白的水平增加。使用 PKR-K296R、TAR RNA 结合蛋白或 PKR-KO 细胞阻断 PKR，可降低 RAN 蛋白水平。p-PKR 在C9orf72 ALS/FTD 人和小鼠大脑中升高，并抑制C9orf72 中的PKR使用 AAV-PKR-K296R 或食品和药物管理局 (FDA) 批准的药物二甲双胍的 BAC 转基因小鼠，减少 RAN 蛋白，并改善行为和病理。总之，靶向 PKR，包括使用二甲双胍，是治疗C9orf72 ALS/FTD 和其他扩展性疾病的一种有前途的治疗方法。