Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, New Cornerstone Science Laboratory, School of Life Sciences, Fudan University, Shanghai, China.
Peninsula Medical School, University of Plymouth, Plymouth, UK.
Nat Chem Biol. 2023 Nov;19(11):1372-1383. doi: 10.1038/s41589-023-01384-5. Epub 2023 Aug 17.
RNA molecules with the expanded CAG repeat (eCAGr) may undergo sol-gel phase transitions, but the functional impact of RNA gelation is completely unknown. Here, we demonstrate that the eCAGr RNA may form cytoplasmic gel-like foci that are rapidly degraded by lysosomes. These RNA foci may significantly reduce the global protein synthesis rate, possibly by sequestering the translation elongation factor eEF2. Disrupting the eCAGr RNA gelation restored the global protein synthesis rate, whereas enhanced gelation exacerbated this phenotype. eEF2 puncta were significantly enhanced in brain slices from a knock-in mouse model and from patients with Huntington's disease, which is a CAG expansion disorder expressing eCAGr RNA. Finally, neuronal expression of the eCAGr RNA by adeno-associated virus injection caused significant behavioral deficits in mice. Our study demonstrates the existence of RNA gelation inside the cells and reveals its functional impact, providing insights into repeat expansion diseases and functional impacts of RNA phase transition.
具有扩展 CAG 重复（eCAGr）的 RNA 分子可能经历溶胶-凝胶相转变，但 RNA 胶凝的功能影响尚完全不清楚。在这里，我们证明 eCAGr RNA 可能形成细胞质凝胶样焦点，这些焦点很快被溶酶体降解。这些 RNA 焦点可能通过隔离翻译延伸因子 eEF2 显著降低全局蛋白质合成率。破坏 eCAGr RNA 胶凝恢复了全局蛋白质合成率，而增强胶凝则加剧了这种表型。在亨廷顿病患者的脑切片和 knock-in 小鼠模型中，eEF2 斑点显著增强，亨廷顿病是一种表达 eCAGr RNA 的 CAG 扩展疾病。最后，腺相关病毒注射引起神经元表达 eCAGr RNA，导致小鼠出现显著的行为缺陷。我们的研究证明了细胞内 RNA 胶凝的存在，并揭示了其功能影响，为重复扩展疾病和 RNA 相变的功能影响提供了新的见解。
