United Kingdom Dementia Research Institute Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
Institute of Molecular Biology and Biophysics, Department of Biology, ETH Zürich, CH-8093, Zürich, Switzerland.
Nat Commun. 2020 Dec 11;11(1):6341. doi: 10.1038/s41467-020-20191-3.
Mutations in the RNA-binding protein Fused in Sarcoma (FUS) cause early-onset amyotrophic lateral sclerosis (ALS). However, a detailed understanding of central RNA targets of FUS and their implications for disease remain elusive. Here, we use a unique blend of crosslinking and immunoprecipitation (CLIP) and NMR spectroscopy to identify and characterise physiological and pathological RNA targets of FUS. We find that U1 snRNA is the primary RNA target of FUS via its interaction with stem-loop 3 and provide atomic details of this RNA-mediated mode of interaction with the U1 snRNP. Furthermore, we show that ALS-associated FUS aberrantly contacts U1 snRNA at the Sm site with its zinc finger and traps snRNP biogenesis intermediates in human and murine motor neurons. Altogether, we present molecular insights into a FUS toxic gain-of-function involving direct and aberrant RNA-binding and strengthen the link between two motor neuron diseases, ALS and spinal muscular atrophy (SMA).
融合肉瘤（FUS）中的 RNA 结合蛋白突变导致早发性肌萎缩侧索硬化症（ALS）。然而，对 FUS 的中枢 RNA 靶标及其对疾病的影响仍难以捉摸。在这里，我们使用交联和免疫沉淀（CLIP）和 NMR 光谱学的独特组合来鉴定和描述 FUS 的生理和病理 RNA 靶标。我们发现 U1 snRNA 是 FUS 的主要 RNA 靶标，通过其与茎环 3 的相互作用，并提供与 U1 snRNP 这种 RNA 介导的相互作用模式的原子细节。此外，我们表明，与 ALS 相关的 FUS 异常地通过其锌指与 U1 snRNA 在 Sm 位点结合，并在人和鼠运动神经元中捕获 snRNP 生物发生中间体。总的来说，我们提出了对 FUS 毒性获得功能的分子见解，涉及直接和异常的 RNA 结合，并加强了两种运动神经元疾病，肌萎缩侧索硬化症（ALS）和脊髓性肌萎缩症（SMA）之间的联系。
