TAR DNA-binding protein 43 (TDP-43) – stress granule protein–protein interfaces (TDP-43–SG interface)

TAR DNA-binding protein 43 (TDP-43) is a critical RNA-binding protein primarily involved in the regulation of RNA splicing, stability, and transport within the nucleus (UniProt Q13148). In neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), TDP-43 undergoes pathological mislocalization to the cytoplasm, where it associates with stress granules (SGs) (Wolozin & Ivanov, 2019). These SGs are transient, membrane-less organelles formed via liquid-liquid phase separation (LLPS) in response to cellular stress (Li et al., 2013). The interface between TDP-43 and other stress granule proteins is a focal point for therapeutic intervention, as persistent or aberrant SG formation is believed to seed the irreversible aggregation of TDP-43, leading to proteotoxicity and neuronal death (Zhang et al., 2020). Current drug development efforts, such as those involving antisense oligonucleotides like BIIB105, focus on modulating these protein-protein interfaces or reducing the expression of proteins that promote TDP-43 aggregation (ClinicalTrials.gov NCT04494256). However, a major challenge lies in selectively targeting pathological interactions without disrupting the essential physiological roles of TDP-43 in RNA metabolism.

Other names

TDP-43TARDBPALS10Stress granule-associated TDP-43TDP-43–SG complex

Modulation of liquid-liquid phase separation (LLPS) and inhibition of pathological protein-protein interactions to prevent or reverse the transition of TDP-43 from dynamic stress granules into irreversible pathological aggregates.