TAR DNA-binding protein 43–UG-rich RNA condensate complex (TDP-43–UG-RNA complex)

The TAR DNA-binding protein 43 (TDP-43)–UG-rich RNA condensate complex is a dynamic ribonucleoprotein assembly essential for cellular RNA metabolism and proteostasis. TDP-43 is a multi-domain protein that specifically binds to UG-rich sequences in the 3' untranslated regions of thousands of messenger RNAs, a process that is critical for its solubility and function (UniProt P06748). This interaction promotes liquid-liquid phase separation (LLPS), enabling the formation of biomolecular condensates such as stress granules and nuclear bodies which regulate RNA splicing, transport, and stability (Mann et al., 2019, Neuron). In neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), TDP-43 dissociates from its RNA targets and transitions from a dynamic liquid state into insoluble, toxic protein aggregates (Neumann et al., 2006, Science). These aggregates lead to a loss of nuclear function and a gain of cytoplasmic toxicity, driving neuronal death. Therapeutic strategies are currently being developed to stabilize the TDP-43–RNA complex or modulate the biophysical properties of these condensates to prevent or reverse pathological aggregation. Such approaches include the use of antisense oligonucleotides (ASOs) to reduce aggregate-prone protein levels and small molecules designed to maintain the protein in its functional, liquid-like state.

Other names

TDP-43–RNA complexTARDBP–UG-rich RNA assemblyTDP-43 ribonucleoprotein complexTDP-43 liquid-liquid phase separation complexTDP-43–UG-rich RNA condensate

Stabilization of the liquid-like state of TDP-43 condensates to prevent pathological phase transition into insoluble aggregates or restoration of RNA-binding affinity to maintain protein solubility and nuclear function.