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

TAR DNA-binding protein 43 (TDP-43) is a critical RNA-binding protein primarily located in the nucleus, where it regulates RNA splicing, transport, and stability (UniProt Q13148). In pathological conditions, TDP-43 misfolds and forms insoluble, hyperphosphorylated aggregates in the cytoplasm, a process associated with the depletion of functional nuclear TDP-43 (Neumann et al., Science, 2006). These aggregates are the primary pathological hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), and they also contribute to Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) (Nelson et al., Brain, 2019). Therapeutic approaches currently under investigation include antisense oligonucleotides to reduce protein levels (e.g., BIIB105, ClinicalTrials.gov NCT04494256), monoclonal antibodies to clear aggregates (e.g., NI-205), and small molecules designed to stabilize the protein's native conformation. A significant challenge in targeting TDP-43 is the protein's essential role in cellular homeostasis; therapies must selectively target toxic species while sparing the functional nuclear pool to prevent detrimental loss-of-function effects (Gao et al., Nature Communications, 2019).

Other names

TARDBPTDP43Pathological TDP-43TDP-43 inclusionsCytoplasmic TDP-43 aggregates

Antisense oligonucleotide-mediated reduction of protein expression, Monoclonal antibody-mediated clearance of pathological aggregates, Small molecule inhibition of protein phosphorylation and ubiquitination, Stabilization of the native monomeric protein state