The Gelation of CAG Repeat Expansion RNAs Suppresses Global Protein Translation

Abstract RNA molecules with the expanded CAG repeat (eCAGr) may undergo liquid-to-gel phase transitions rapidly, but the nuclear eCAGr RNA foci display liquid-like properties, different from their gel-like behaviour in vitro (ref.1). The functional impact of this RNA gelation is also completely unknown (ref.2). Here we demonstrate that eCAGr RNA may form gel-like condensates (foci) in the cytoplasm that were rapidly degraded by lysosomes in a LAMP2-dependent manner. These RNA foci may lead to a drastic reduction of the global protein synthesis rate in cells and in vitro, possibly by sequestering the key protein translation elongation factor eEF2, which formed puncta colocalizing or surrounding the cytoplasmic eCAGr RNA condensates. Disrupting the eCAGr RNA gelation partially restored the global protein translation rate whereas the induction of enhanced gelation by an optogenetic system exacerbated this phenotype. Finally, eEF2 puncta were significantly enhanced in brain slices from a mouse model and patients of Huntington’s disease, which is a CAG expansion disorder expressing eCAGr RNAs. Our study demonstrates the RNA gelation inside the cells and reveals its functional impact, providing new angles for understanding pathological mechanisms of repeat expansion diseases and global protein translation regulation.