It consists of four domains: an N-terminal domain spanning residues 1–76 (NTD) with a well-defined fold that has been shown to form a dimer or oligomer;[6][7] two highly conserved folded RNA recognition motifs spanning residues 106–176 (RRM1) and 191–259 (RRM2), respectively, required to bind target RNA and DNA;[8] an unstructured C-terminal domain encompassing residues 274–414 (CTD), which contains a glycine-rich region, is involved in protein-protein interactions, and harbors most of the mutations associated with familial amyotrophic lateral sclerosis.

[16] All of this raises the possibility that NTD and the RNA recognition motifs (later on defined) could cooperatively interact with nucleic acids to accomplish TDP-43's physiological functions.

[21] The nuclear export signal is located between residues 239 and 251 sequence probably bears a role in TDP-43's shuttling function, and was recently found using a prediction algorithm.

[23] PLDs are low complexity sequences that have been reported to mediate gene regulation via Liquid-Liquid Phase Transition (LLP) thus driving RNP granule assembly.

Mutations within the TDP-43 proteins Glycine Rich Region (GRR) have recently been identified as associates that can contribute to various neurodegenerative diseases, with the most notable and common NDD being ALS, about 10% of the mutations causing familial ALS are accredited with the TDP-43 protein [25] This CTD is often reported to play important role in pathogenic behavior of TDP-43: RNPs granules could have a role in stress response, and thus, aging, or persistence stress could lead the LLPs to turn into irreversible Liquid Solid Phase separation, pathological aggregates notably found in ALS neurons.

[29] TDP-43 has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation.

[31][32] In spinal motor neurons TDP-43 has also been shown in humans to be a low molecular weight neurofilament (hNFL) mRNA-binding protein.

[35] TDP-43 protein is a key element of the non-homologous end joining (NHEJ) enzymatic pathway that repairs DNA double-strand breaks (DSBs) in pluripotent stem cell-derived motor neurons.

In TDP-43 depleted human neural stem cell-derived motor neurons, as well as in sporadic ALS patients' spinal cord specimens there is significant DSB accumulation and reduced levels of NHEJ.

[36] A hyper-phosphorylated, ubiquitinated and cleaved form of TDP-43—known as pathologic TDP43—is the major disease protein in ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal dementia (FTLD-TDP, previously referred to as FTLD-U[37]) and in amyotrophic lateral sclerosis (ALS).

[40] Abnormalities of TDP-43 also occur in an important subset of Alzheimer's disease patients, correlating with clinical and neuropathologic features indexes.

[41] Misfolded TDP-43 is found in the brains of older adults over age 85 with limbic-predominant age-related TDP-43 encephalopathy, (LATE), a form of dementia.

[42] Mutations in the TARDBP gene are associated with neurodegenerative disorders including frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS).

[49] A recent study has demonstrated that cellular stress can trigger the abnormal cytoplasmic mislocalisation of TDP-43 in spinal motor neurons in vivo, providing insight into how TDP-43 pathology may develop in sporadic ALS patients.