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

TAR DNA-binding protein 43 (TDP-43) is a highly conserved RNA-binding protein that normally resides in the nucleus, where it regulates transcription, RNA splicing, and mRNA stability (UniProt Q13148). In pathological states, TDP-43 undergoes a liquid-to-solid phase transition, forming insoluble, hyperphosphorylated, and ubiquitinated aggregates in the cytoplasm of neurons and glial cells (Neumann et al., 2006, Science, PMID: 17023659). This proteinopathy is a hallmark of nearly all cases of amyotrophic lateral sclerosis (ALS) and approximately half of frontotemporal lobar degeneration (FTLD) cases, as well as being increasingly recognized in Alzheimer's disease and Limbic-predominant age-related TDP-43 encephalopathy (LATE) (Nelson et al., 2019, Brain, PMID: 31036292). Therapeutic strategies focus on reducing the expression of TDP-43 using antisense oligonucleotides like BIIB105, promoting the clearance of toxic aggregates via immunotherapy such as ACI-5885, and restoring the protein's essential nuclear functions (ClinicalTrials.gov NCT04494256; AC Immune). However, because TDP-43 is vital for cellular homeostasis, drug development must carefully balance the elimination of toxic species with the preservation of normal physiological activity. Successful targeting of pathological TDP-43 represents a major frontier in treating neurodegenerative diseases characterized by protein misfolding.

Other names

TARDBPTDP43Pathological TDP-43Phosphorylated TDP-43pTDP-43TDP-43 aggregates

Therapeutic approaches include antisense oligonucleotides (ASOs) to reduce total or ataxin-2 mediated TDP-43 toxicity, small molecule inhibitors of PIKFYVE to enhance autophagic clearance, and monoclonal antibodies designed to neutralize extracellular seeds or promote intracellular degradation of aggregates.