RNA Structural Biology of Neurodegeneration: Phase Separation, Phase Transition, and Proteinopathy

Neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, are becoming increasingly prevalent in super-aging societies. However, the molecular mechanisms by which prion-like proteins undergo aberrant phase transition, aggregation, and propagation during neurodegeneration remain incompletely understood. Although these proteins are capable of undergoing liquid-liquid phase separation (LLPS) followed by a sol-gel transition in vitro, the factors that govern their pathological phase transition in vivo remain largely elusive. Notably, many prion-like proteins also possess RNA-binding properties, and accumulating evidence indicates that RNA plays pivotal roles in regulating both LLPS and the subsequent transition to more solid-like states. In this review, we summarize recent advances in the RNA structural biology of neurodegeneration, with particular emphasis on RNA G-quadruplexes (rG4s) as pathological determinants, and discuss emerging mechanisms by which RNA structures promote the phase transition and proteinopathy of prion-like proteins.