RNA structure promotes liquid-to-solid phase transition of short RNAs in neuronal dysfunction

Abstract

In nucleotide expansion disorders, RNA foci are reportedly associated with neurodegenerative disease pathogeneses. Characteristically, these RNAs exhibit long poly-RNA repeats, such as 47 × CAG, 47 × CUG, or 29 × GGGGCC, usually becoming abnormal pathological aggregations above a critical number of nucleotide repeats. However, it remains unclear whether short, predominantly cellular RNA molecules can cause phase transitions to induce RNA foci. Herein, we demonstrated that short RNAs even with only two repeats can aggregate into a solid-like state via special RNA G-quadruplex structures. In human cells, these solid RNA foci could not dissolve even when using agents that disrupt RNA gelation. The aggregation of shorter RNAs can be clearly observed in vivo. Furthermore, we found that RNA foci induce colocalization of the RNA-binding protein Sam68, a protein commonly found in patients with fragile X-associated tremor/ataxia syndrome, suppressing cell clonogenicity and eventually causing cell death. Our results suggest that short RNA gelation promoted by specific RNA structures contribute to the neurological diseases, which disturb functional cellular processes.

Spotlight on G-Quadruplexes: From Structure and Modulation to Physiological and Pathological Roles

“…Another intriguing example is their involvement in phase separation, as structured G-quadruplexes in C9ORF72 mRNA were found to induce stress granule assembly [ 267 ]. Similarly, a recent study by Wang and Xu demonstrated that short RNA molecules bearing CGG or telomeric repeats aggregate into solid state foci, both in vitro and in vivo, through the formation of intermolecular higher-order G-quadruplex structures [ 268 ]. Furthermore, RNA G-quadruplexes have been shown to have a direct effect on translation itself, for example, by preventing recruitment of the 43S ribosome and reducing translation efficiency unless unwound by the translation initiation factor eIF4A [ 269 ].…”

“…Indeed, it was recently demonstrated that even short G-rich RNAs drive liquid-to-solid phase transition through the self-assembly capabilities of G-quadruplex structures. The resulting RNA foci induced cell dysfunction and death, suggesting an alternative molecular pathway behind the pathophysiology of repeat expansion disorders [ 268 ]. Overall, expansion of G-quadruplexes was clearly designated as the causal factor in ALS and FTD using cellular models and patient-derived tissue samples.…”