The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine–arginine and proline–arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD.

与 C9orf72 中GGGGCC重复扩增相关的肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的确切机制目前还不清楚。两种功能获得机制是可能的：重复 RNA 毒性和二肽重复蛋白 (DPR) 毒性。我们在这里使用 ALS 的斑马鱼模型剖析了这两种可能性。甘氨酸-精氨酸和脯氨酸-精氨酸这两种 DPR 的表达诱导了运动性轴索病。同样，扩展的正义和反义重复 RNA 也诱导运动轴索病并主要形成细胞质 RNA 病灶。但是，在这些条件下未检测到 DPR。此外，终止密码子中断的重复 RNA 仍然诱导运动轴索病，并且排除了低水平 DPR 的协同作用。总之，这些结果表明重复 RNA 毒性与 DPR 的形成无关。这种 RNA 毒性，但不是 DPR 毒性，被 RNA 结合蛋白 Pur-alpha 和自噬相关蛋白 p62 减弱。C9orf72相关的ALS/FTD。