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

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.