Hangzhou Talk #14 | Session Chair
The Gelation of Cytoplasmic CAG Repeat Expansion RNAs Suppresses Global Protein Translation
RNA molecules with the expanded CAG repeat (eCAGr) may undergo sol-gel phase transitions in vitro, but the cellular presence and functional impact of RNA gelation is unclear. Here, we demonstrate that eCAGr RNA may form cytoplasmic gel-like foci that were rapidly degraded by lysosomes in a LAMP2C-dependent manner. These RNA foci may cause a significant reduction of the global protein synthesis rate in cells and in vitro, possibly by sequestering the protein translation elongation factor eEF2. Disrupting the eCAGr RNA gelation restored the global protein synthesis rate, whereas enhanced gelation induced by an optogenetic system exacerbated this phenotype. eEF2 puncta were significantly enhanced in brain slices from a knockin mouse model and patients of Huntington’s disease, which is a CAG expansion disorder expressing the eCAGr RNA. Finally, neuronal expression of the eCAGr RNA by AAV injection caused significant behavioral deficits and electrophysiological changes in vivo in the mouse model. Our study demonstrates the existence of RNA gelation inside the cells and reveals its functional impact, providing new mechanistic insights into repeat expansion diseases and global protein synthesis regulation.
