Gelation of cytoplasmic expanded CAG RNA repeats suppresses global protein synthesis

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.

Automated summary

RNA molecules with expanded CAG repeats (eCAGr) can form gel-like foci in the cytoplasm, which are degraded by lysosomes. These RNA foci can significantly reduce global protein synthesis by sequestering the translation elongation factor eEF2. Disrupting RNA gelation restores protein synthesis, while enhancing gelation exacerbates this phenotype. Our study reveals the functional impact of RNA gelation and its association with repeat expansion diseases and RNA phase transition.