A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(G 4 C 2 ) exp , causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G 4 C 2 ) exp and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a small molecule diminishes intron retention caused by the r(G 4 C 2 ) exp and allows the liberated intron to be eliminated by the nuclear RNA exosome, a multi-subunit degradation complex. Our findings highlight the complexity of mechanisms available to RNA-binding small molecules to alleviate disease pathologies and establishes a pipeline for the design of brain penetrant small molecules targeting RNA with novel modes of action in vivo.

中文翻译：

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一种血脑渗透性 RNA 靶向小分子通过核 RNA 外泌体触发 c9ALS/FTD 中 r(G 4 C 2 ) exp 的消除

内含子 1 中的六核苷酸重复扩增C9orf72基因是肌萎缩侧索硬化症和额颞叶痴呆或 c9ALS/FTD 最常见的遗传原因。从扩展中转录的 RNA，r(G4个C2个)exp，导致各种病理，包括内含子保留、产生有毒二肽重复蛋白 (DPR) 的异常翻译，以及 RNA 病灶中 RNA 结合蛋白 (RBP) 的螯合。在这里，我们描述了一种小分子，它能与 r(G4个C2个)exp并减轻从 c9ALS 患者衍生的诱导多能干细胞 (iPSC) 和两个 c9ALS/FTD 小鼠模型中分化出来的脊髓神经元的疾病病理。这些研究揭示了一种作用模式，通过这种模式，小分子减少了由 r(G4个C2个)exp并允许释放的内含子被核 RNA 外泌体（一种多亚基降解复合物）消除。我们的研究结果强调了可用于 RNA 结合小分子以减轻疾病病理的机制的复杂性，并为设计具有新体内作用模式的 RNA 的脑渗透小分子建立了管道。