ORCID
- Luo, Shouqing: 0000-0002-7998-3059
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.
DOI
10.1038/s41589-023-01384-5
Publication Date
2023-11-01
Publication Title
Nature Chemical Biology
Volume
19
Issue
11
ISSN
1552-4450
Embargo Period
2024-02-16
Organisational Unit
Peninsula Medical School
First Page
1372
Last Page
1383
Recommended Citation
Pan, Y., Lu, J., Feng, X., Lu, S., Yang, Y., Yang, G., Tan, S., Wang, L., Li, P., Luo, S., & Lu, B. (2023) 'Gelation of cytoplasmic expanded CAG RNA repeats suppresses global protein synthesis', Nature Chemical Biology, 19(11), pp. 1372-1383. Available at: https://doi.org/10.1038/s41589-023-01384-5
