RNA G-Quadruplexes Facilitate RNA Accumulation in G-Rich Repeat Expansions

The regulatory mechanisms of the processes of RNA accumulation were examined from a chemical perspective in repeat-expansion disorders, which induce cytotoxicity and cause neurodegenerative diseases. We found that the accumulation, including production, gelation, and sedimentation, of RNA repeats transcribed from repeat expansions related to neurodegenerative diseases was greatly accelerated by G-quadruplex-forming RNA repeats, although no acceleration was induced by hairpin-forming RNA repeats. We also investigated the relationship between accumulation and physical solution properties, such as viscosity and water activity, and found that RNA accumulation was promoted through a decrease in the dielectric constant. Importantly, we found that the RNA accumulation required RNA G-quadruplexes and was promoted by changes in the dielectric property of the cell induced by an ion channel inhibitor. Our study is the first to show that the accumulation processes that induce toxicity in cells can be controlled via electrostatic interactions in the RNA G-quadruplex; thus, these can form the basis of guidelines for the chemical control of cell toxins.