transactive response (TAR) DNA-binding protein 43; TDP-43 (TARDBP TDP43)

Function

• DNA-binding protein & RNA-binding protein
• regulates transcription & splicing
• binds specifically to pyrimidine-rich motifs of TAR DNA & to single stranded TG repeated sequences
• binds to RNA, specifically to UG repeated sequences with a minimun of 6 contiguous repeats
• involved in the regulation of CFTR splicing
• may also be involved in microRNA biogenesis, apoptosis & cell division.

Structure

• contains 2 RRM domains (RNA recognition motif)

Compartment

nucleus

Expression

• ubiquitously expressed
• expression is high in pancreas, placenta, lung, genital tract & spleen

Pathology

• can repress HIV-1 transcription by binding to the HIV-1 long terminal repeat
• role in the regulation of CFTR splicing
  • promotes CFTR exon 9 skipping by binding to the UG repeated motifs in the polymorphic region near the 3' splice site
  • this aberrant splicing is associated with pathological features typical of cystic fibrosis
• hyperphosphorylated, ubiquitinated & cleaved to generate C-terminal fragments in hippocampus, neocortex & spinal cord of patients with amyotrophic lateral sclerosis (ALS)
• absent from the nucleus of affected neurons in ALS but is the primary component of cytoplasmic ubiquitin-positive inclusion bodies
• defects in TARDBP are the cause of ALS type 10
• found in inclusions & neurites of patients with chronic traumatic encephalopathy
• deposited in brain of patients with frontotemporal dementia (FTD) associated with motor neuron disease
• associated with proteinopathy in over 20% of people > 80 years, limbic-predominant age-related TDP-43 encephalopathy (LATE) & limbic-predominant amnestic neurodegenerative syndrome (LANS)
• a misfolded protein relatively common in association with other misfolded proteins amyloid-beta, PHF-tau, & alpha-synuclein in older adults
  • the 4 misfolded proteins appear associated with cognitive impairment that typically progresses to severe dementia

More general terms

• RNA-binding protein
• DNA-binding protein
• phosphoprotein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=23435
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:23435
• OMIM: https://mirror.omim.org/entry/605078
• OMIM: https://mirror.omim.org/entry/612069
• UniProt: http://www.uniprot.org/uniprot/Q13148.html