Department of Chemistry, The Scripps Research Institute and UF Scripps Biomedical Research, University of Florida, Jupiter, FL 33458.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224.
Proc Natl Acad Sci U S A. 2022 Nov 29;119(48):e2210532119. doi: 10.1073/pnas.2210532119. Epub 2022 Nov 21.
A hexanucleotide repeat expansion in intron 1 of the gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(GC), 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(GC) 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(GC) 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.
基因内含子 1 中的六核苷酸重复扩展是肌萎缩侧索硬化症和额颞叶痴呆（或 c9ALS/FTD）的最常见遗传原因。从扩展转录而来的 RNA，r(GC)，导致各种病理，包括内含子保留、产生毒性二肽重复蛋白 (DPR) 的异常翻译，以及 RNA 结合蛋白 (RBP) 在 RNA 焦点中的隔离。在这里，我们描述了一种小分子，它可以与 r(GC) 强烈且选择性地相互作用，并减轻源自 c9ALS 患者衍生的诱导多能干细胞 (iPSC) 的脊髓神经元和两种 c9ALS/FTD 小鼠模型中的疾病病理。这些研究揭示了一种作用模式，其中小分子可减轻 r(GC) 引起的内含子保留，并允许释放的内含子被核 RNA 外切体（一种多亚基降解复合物）消除。我们的发现强调了 RNA 结合小分子可用于减轻疾病病理的机制的复杂性，并为设计针对 RNA 的具有新型作用模式的脑穿透小分子建立了一个管道。
