Defining RNA Oligonucleotides that Reverse Deleterious Phase Transitions of RNA-binding Proteins with Prion-like Domains

Dr. Lin Guo, Associate Professor in the Department of Biochemistry and Molecular Biology, and her colleagues have recently discovered a novel mechanism by which RNA molecules modulate protein behavior. This research explores the pathological phase transitions of RNA-binding proteins that are linked to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The study, which was published recently in Molecular Cell, reveals that specific short RNA oligonucleotides can act as molecular chaperones to prevent and reverse the formation of toxic protein aggregates. The authors focused on FUS and TDP-43, two prion-like proteins whose accumulation in the cytoplasm and subsequent loss of nuclear function are hallmarks of these ALS and FTD. They show that these short RNAs effectively dissolve toxic assemblies, restore the proper nuclear localization of FUS and TDP-43, thereby mitigating cellular toxicity. The study further reveals that the RNA’s sequence, length, and structure are the critical factors that determine its chaperone activity. These properties work by restricting the multivalent protein-RNA interactions that would otherwise drive aberrant condensation. Thus, the ability to prevent protein instability is determined by the precise design of the RNA molecule itself. This means that by defining these specific design principles, the work provides new insight into restoring proteostasis at the molecular level and establishes a foundation for developing novel RNA-based therapeutic strategies.