TDP43

TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed RNA-binding protein encoded by the TARDBP gene. In humans it comprises about 414 amino acids and a molecular weight of roughly 43 kDa. The protein features an N-terminal domain that supports dimerization, two RNA recognition motifs (RRM1 and RRM2) that bind UG-rich RNA sequences, and a C-terminal glycine-rich region with prion-like properties. TDP-43 normally localizes mainly to the nucleus and shuttles between nucleus and cytoplasm to participate in various aspects of RNA metabolism.

Normal functions of TDP-43 include regulation of transcription, pre-mRNA splicing, mRNA stability and transport, and microRNA processing. It also participates in stress granule dynamics and may influence RNA transport and local translation in neurons. Through these roles, TDP-43 helps control gene expression programs critical for neuronal health and response to cellular stress.

Pathology emerges when TDP-43 mislocalizes to the cytoplasm, where it forms ubiquitin- and phosphorylated-inclusions and can be cleaved into C-terminal fragments that aggregate. This pathology is a hallmark of the vast majority of amyotrophic lateral sclerosis (ALS) cases and most forms of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). The disease process is thought to involve both loss of normal nuclear TDP-43 function and a toxic gain of cytoplasmic aggregate function. TARDBP mutations are linked to a minority of familial ALS and, less commonly, to FTLD.

Research continues to elucidate how mislocalization and aggregation drive neurodegeneration and to develop strategies that restore nuclear TDP-43 function or prevent its aggregation.