BPS2026 – Heterogeneous aging of RNA condensates

RNA condensates formed through homotypic RNA-RNA interactions represent a critical class of biomolecular assemblies with significant pathological implications in neurodegenerative diseases including Huntington’s disease (HD), and frontotemporal dementia (FTD). These assemblies arise via liquid-liquid phase separation driven by multivalent base-pairing interactions when nucleotide repeats exceed critical thresholds. Using molecular dynamics simulations of CAG-repeat RNA condensates, we demonstrate that they exhibit distinct spatio-temporal evolution, with different regions undergoing different aging processes at different rates. We evidence high-affinity RNA-RNA interactions promote the formation of irreversible arrested aggregation at the core surrounded by fluid shells, giving rise to a core-shell architecture. Our results also reveal that both configurational properties (base-pairing strength and molecular size) and orientational properties (nematic order and asphericity) vary heterogeneously across spatial and temporal scales. Our work establishes a direct link between RNA sequences, spatial and temporal heterogeneous aging, and the emergence of pathological like irreversible aggregation.