Dysregulation of Stress Granule Dynamics in ALS

초록

RNA binding proteins (RBPs) play key roles throughout the entire RNA life cycle, functioning in both the nucleus and cytoplasm to control various aspects of RNA metabolism such as splicing, polyadenylation, editing, transport, translation, and degradation. These RBPs constitute the core components of stress granules (SGs), which assemble rapidly through dynamic interactions under cellular stress. Dysregulation of RBPs such as TDP-43, FUS, ANXA11—known to affect SGs dynamics—have been identified as risk factors for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Under physiological conditions, these proteins undergo liquid-liquid phase separation (LLPS) to form functional biomolecular condensates. However, under pathological conditions—including gene mutations, post-translational modifications, environmental stress, and aging—this process can become dysregulated, transitioning from a liquid-like to a solid-like state, thereby promoting irreversible and cytotoxic protein aggregation. The accumulation of pathogenic protein aggregates in specific brain regions is thought to be associated with both toxic gain-of-function and loss-of-function mechanisms, ultimately leading to neuronal impairment and cell death. Consequently, therapeutic approaches aimed at refolding or re-localizing misfolded or aggregated proteins back to their native, functional states may offer a more effective means of mitigating neurotoxicity by concurrently addressing both toxic mechanisms, rather than merely removing the aggregates. RNA, a shared ligand among many disease-associated RNA-binding proteins (RBPs), plays a central role in SGs dynamics and has been shown to significantly influence RBPs phase transition behavior. While initial studies pointed to a generally cooperative role of RNA in promoting RBP phase separation and the formation of SGs, more recent findings reveal that RNA may also regulate phase separation under specific physiological or disease-related conditions. In this presentation, I will discuss potential therapeutic RNAs (small RNAs, circRNAs) that can modulate cellular condensation of RBPs