Science Spotlight: Making TDP-43 aggregation-resistant

A team led by James Shorter at the University of Pennsylvania uncovered a potentially druggable allosteric mechanism for preventing and reversing pathological TDP-43 aggregation, a hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease.

The team showed that short RNA molecules resembling FDA-approved antisense oligonucleotides in size and chemistry can stabilize RNA recognition motifs in TDP-43 while destabilizing an aggregation-prone helical region in its prion-like domain, effectively remodeling the protein into soluble, functional conformers...