Gelation of cytoplasmic expanded CAG RNA repeats suppresses global protein synthesis

Yuyin Pan, J Lu, Xinran Feng, S Lu, Y Yang, G Yang, Shudan Tan, Liang Wang, Pilong Li, Shouqing Luo*, B Lu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

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.
Original languageEnglish
Pages (from-to)1372-1383
Number of pages0
JournalNature Chemical Biology
Volume19
Issue number11
Early online date17 Aug 2023
DOIs
Publication statusPublished - Nov 2023

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