TAR DNA-binding protein 43 (TDP-43) pathological condensate (TDP-43 pathological condensate)

TAR DNA-binding protein 43 (TDP-43) is a critical RNA-binding protein primarily located in the nucleus, where it regulates essential processes such as alternative splicing, mRNA stability, and transcriptional repression (Source: UniProt P15502). In neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), TDP-43 undergoes a pathological transition from its soluble state into liquid-liquid phase-separated (LLPS) condensates and eventually into insoluble cytoplasmic aggregates (Source: Gasset-Rosa et al., 2019, Neuron). These pathological condensates are considered a primary driver of disease through a dual mechanism: the loss of essential nuclear functions and the gain of cytoplasmic toxicity that disrupts cellular proteostasis and nucleocytoplasmic transport (Source: Portz et al., 2021, Cell). Therapeutic strategies targeting TDP-43 pathological condensates focus on preventing the initial phase separation, promoting the clearance of existing aggregates via autophagy, or reducing the expression of TDP-43 and its assembly-promoting partners like Ataxin-2 (Source: Biogen, BIIB105). Current drug development efforts include antisense oligonucleotides and small molecule inhibitors of kinases like PIKfyve that modulate the endolysosomal pathway to clear TDP-43 inclusions (Source: Verge Genomics, VRG50635).

Other names

TDP-43 aggregatesTDP-43 inclusionsTDP-43 liquid-liquid phase separationTDP-43 LLPSTARDBP aggregates

Inhibition of liquid-liquid phase separation, promotion of aggregate clearance via autophagy, and reduction of protein expression through antisense oligonucleotides or modulation of assembly-promoting factors.