TARDBP

TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa), is a is_associated_with::protein that in humans is encoded by the TARDBP is_associated_with::gene.

Function
TDP-43 is a transcriptional is_associated_with::repressor that binds to chromosomally integrated TAR DNA and represses is_associated_with::HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. In particular, TDP-43 is a splicing factor binding to the intron8/exon9 junction of the CFTR gene and to the intron2/exon3 region of the apoA-II gene. A similar pseudogene is present on chromosome 20.

TDP-43 has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation. Recent work has characterized the transcriptome-wide binding sites revealing that thousands of RNAs are bound by TDP-43 in neurons.

TDP-43 was originally identified as a transcriptional repressor that binds to chromosomally integrated trans-activation response element (TAR) DNA and represses is_associated_with::HIV-1 transcription. It was also reported to regulate alternate splicing of the CFTR gene and the apoA-II gene.

In spinal motor neurons TDP-43 has also been shown in humans to be a low molecular weight microfilament (hNFL) mRNA-binding protein. It has also shown to be a is_associated_with::neuronal activity response factor in the dendrites of hippocampal neurons suggesting possible roles in regulating mRNA stability, transport and local translation in neurons.

Clinical significance
Hyper-phosphorylated, is_associated_with::ubiquitinated and cleaved form of TDP-43, known as pathologic TDP43, is the major disease protein in is_associated_with::ubiquitin-positive, tau-, and is_associated_with::alpha-synuclein-negative is_associated_with::frontotemporal dementia (FTLD-TDP, previously referred to as FTLD-U ) and in is_associated_with::Amyotrophic lateral sclerosis (ALS). Elevated levels of the TDP-43 protein have also been identified in individuals diagnosed with is_associated_with::chronic traumatic encephalopathy, a condition that often mimics ALS and that has been associated with athletes who have experienced multiple is_associated_with::concussions and other types of is_associated_with::head injury. Abnormalities of TDP-43 also occur in an important subset of is_associated_with::Alzheimer's disease patients, correlating with clinical and neuropathologic features indexes.

is_associated_with::HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an is_associated_with::RNA is_associated_with::genome that produces a chromosomally integrated is_associated_with::DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator "Tat" is dependent on an RNA regulatory element (TAR) located "downstream" (i.e. to-be transcribed at a later point in time) of the transcription initiation site.

Mutations in the TARDBP gene are associated with neurodegenerative disorders including is_associated_with::frontotemporal lobar degeneration and is_associated_with::amyotrophic lateral sclerosis (ALS). In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS. Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.