RNA-mediated aggregation mechanism of prion-like proteins and its application to drug discovery

Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease are on the rise in super-aging societies. However, the mechanisms underlying the aggregation and propagation of prion-like proteins such as α-synuclein and Tau that contribute to the pathogenesis of neurodegeneration remain poorly understood. Although prion-like proteins are known to undergo liquid-liquid phase separation (LLPS) followed by a sol-gel transition in vitro, the key factors governing their phase transition remain to be elucidated in vivo. Most prion-like proteins are classified as RNA-binding proteins, and recent studies suggest that RNA plays a critical role in mediating both LLPS and the subsequent sol-gel transition of these proteins. In the review, we summarized our findings on RNA G-quadruplexes (rG4s) as a pathological key molecule in neurodegenerative disorders and introduce recent advances in RNA-induced phase transition of prion-like proteins.