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FLASH GENE
Symbol TARDBP contributors: shn/mct - updated : 12-01-2022
HGNC name TAR DNA binding protein
HGNC id 11571
Corresponding disease
ALS10 amyotrophic lateral sclerosis 10
Location 1p36.22      Physical location : 11.072.678 - 11.085.548
Synonym name
  • TAR DNA-binding protein-43
  • Transactive response DNA-binding protein 43 kDa
    • Synonym symbol(s) TDP43, TDP-43, ALS10
    DNA
    TYPE functioning gene
    STRUCTURE 12.87 kb     6 Exon(s)
    Genomic sequence alignment details
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    text structure
  • region spanning nucleotides 451-230 upstream from the transcription start site is the minimal region with a significant transcription activity
    • MAPPING cloned Y linked N status provisional
    Map pter - D1S2736 - D1S1635 - TARDBP - D1S2667 - D1S2740 - cen
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    6 - 4236 43 414 - 2009 19383787
  • major component of the predominately cytoplasmic inclusions observed in ALS and FTLD with ubiquitin-positive inclusions (FTLD-U), the most common form of FTLD
  • exons 2 to 6
    		•
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   lowly Homo sapiensAdultNM_007375
    Digestiveliver   lowly Homo sapiensAdultNM_007375
    Endocrinepancreas   lowly Homo sapiensAdultNM_007375
    Nervousbrain   lowly Homo sapiensAdultNM_007375
    Reproductivefemale systemplacenta  moderately Homo sapiensAdultNM_007375
    Respiratorylung   lowly Homo sapiensAdultNM_007375
    Urinarykidney   moderately Homo sapiensAdultNM_007375
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscular   highly Homo sapiensAdultNM_007375
    cell lineage
    cell lines HeLa
    fluid/secretion
    at STAGE
    physiological period growth/childhood
    Text developmentally regulated in postnatal brain development
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal QGSY-rich region, and contains an independently
    • folded structural domain (NTD), promoting TARDBP oligomerization in a concentration-dependent manner
  • two highly conserved RNA recognition motifs (RRM1 and RRM2) flanked by the N-terminal and the C-terminal tail
  • a nuclear localization signal (NLS)
  • a nuclear export signal (NES)
  • potential acetylation, sumoylation and phosphorylation sites
  • three caspases-3 cleavage sites
  • a hydrophobic patch (AAs 318-343) as the amyloidogenic core essential for TARDBP aggregation
  • two RNA binding domains (RBD)
  • multiple RGG repeats, which are extensively dimethylated at arginine residues (138)
  • C-terminal tail containing a glycine-rich region often found to mediate protein–protein interactions (Zhang 2009), and a zinc finger motif (C-terminal fragments were excluded from TARDBP RNP complexes but retained interaction with FUS/TLS, suggesting that the accumulation of such fragments may compromise TARDBP-FUS/TLS complex function) , and required for self-regulation
    • HOMOLOGY
    interspecies ortholog to Tardbp, Mus musculus
    ortholog to Tardbp, Rattus norvegic us
    ortholog to tardbp, Danio rerio
    ortholog to tardbp, Xenopus laevis
    Homologene
    FAMILY
    CATEGORY regulatory , RNA associated , transport
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic,granule
    intracellular,nucleus,nucleoplasm,nuclear bodies,coiled bodies (Cajal)
    text
  • in control motor neurons, TDP43 is almost exclusively nuclear, whereas in ALS spinal motor neurons, TDP43 is predominantly localized to the cytosol
  • normally, a nuclear protein but neurons with cytoplasmic inclusions have a substantial loss of nuclear TARDBP, suggesting it redistributes to the cytoplasm (Zhang 2009)
  • also present in the cytosol where they are involved in diverse aspects of RNA metabolism, regulating the spatiotemporal fate of mRNA, i.e. subcellular localization, translation or degradation (Lagier-tourenne 2010)
  • in healthy cells, TARDBP is mainly localized to the nucleus, and in the majority of ALS cases, is depleted from the nucleus of motor neurons, and hyperphosphorylated and ubiquitinated TARDBP C-terminal fragments (CTFs) accumulate in insoluble cytoplasmic aggregates
  • predominantly located in the nucleus as a dimer
  • cytosolic accumulation of TARDBP may be a coping mechanism to alleviate or temporarily delay the effects of TARDBP on aberrant mRNA
  • associates with nuclear bodies including Gemini of coiled bodies (GEMs)
    • basic FUNCTION
  • transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription
  • regulating alternate splicing of the CFTR and apoA-II genes
  • capable of binding DNA and RNA, which regulates transcription and splicing but may also be involved in microRNA biogenesis, apoptosis and cell division
  • regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 (CDK6)expression
  • major protein present in the hallmark inclusion bodies of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), suggesting a role for transcriptional dysregulation in FTLD-U pathophysiology
  • could act as a transcriptional repressor, translational repressor as well as a splicing factor promoting the exon 9 exclusion of the CFTR pre-mRNA and could promote the inclusion of exon 7 during splicing of the SMN2 pre-mRNA
  • multifunctional RNA-binding protein for a diverse set of cellular activities
  • heterogeneous nuclear ribonucleoprotein that functions in RNA transcription and pre-mRNA splicing
  • might be involved in the transport of mRNAs to synaptic sites, where active translation of the transported mRNAs occurs
  • functions in regulating transcription and alternative splicing
  • unique NEFL mRNA-binding protein that is altered in its somatotopic localization in ALS spinal motor neurons and potentially contributes to the formation of NF aggregates in ALS
  • may regulates the activities of Rho family members through protein geranylgeranylation
  • DNA/RNA-binding protein implicated in multiple steps of transcriptional and post-transcriptional regulation of gene expression
  • with FUS may play roles in micro-RNA (miRNA) processing
  • TARDBP and FUS implicated in neurodegeneration through errors in multiple steps of RNA processing
  • critical for fat metabolism and embryonic stem cell survival
  • physiological role for TARDBP in regulating body fat and regulate TBC1D1 a gene associated with human obesity)
  • critical role in controlling the formation of SMN-associated GEMs (Gemini of coiled bodies) that may impact on RNA metabolism in motor neurons
  • roles in regulation of RNA splicing and RNA transcription of a subset of genes, including those members of the neurofilament family
  • crucial for the maintenance of neuronal physiology, including that of motor neurons
  • direct role for its aggregation in ALS pathogenesis
  • with FUS/TLS operate together in a common biochemical pathway
  • regulates expression of HDAC6, which plays key roles in autophagic clearance of protein aggregates and is linked to suppression of neurodegeneration
  • its cellular levels are under tight control and it is likely that disease-associated TARDBP aggregates disrupt its self-regulation, thus contributing to pathogenesis
  • RNA/DNA-binding protein implicated in transcriptional and posttranscriptional regulation
  • TARDBP -induced death is associated with the increase of BCL2L11 expression and the decrease of BCL2L1 expression
  • facilitates the production of a subset of precursor miRNAs and promotes the processing of these pre-miRNAs via binding to their terminal loops
  • involved in miRNA biogenesis that is indispensable for neuronal outgrowth
  • potential role in the regulation of axonal growth, suggesting that impairment in the post-transcriptional regulation of mRNAs in the cytoplasm of motor neurons may be a major factor in the development of ALS
  • potential functional role in the regulation of mRNA fate in motor neuron axons
  • associates with stalled ribosomes and contributes to cell survival during cellular stress
  • contributes to Gemini of coiled bodies formation and the biogenesis of U snRNAs, particularly U12 snRNA, in tissues affected by ALS
  • nuclear TARDBP contributes to the autoregulation, suggesting that the absence of nuclear TARDBP induces an abnormal autoregulation and increases the amount of TARDBP mRNA
  • TARDBP proteinopathies induce impairment in the ubiquitin proteasome system (UPS), as evidenced by an accumulation of ubiquitinated proteins and a reduction in proteasome activity in neuronal cells
  • intranuclear protein involved in RNA splicing, trafficking, stabilization, and thus, the regulation of gene expression
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS nervous system , cellular trafficking transport
    text
  • posttranscriptional regulation of miRNA expression in both the nucleus and the cytoplasm
    • PATHWAY
    metabolism
    signaling
  • TDP-43 is a pathological signature protein in different neurodegenerative diseases, ranging from FLTD-U and ALS to AD
  • insulin/IGF1 pathway regulates the clearance of misfolded and aggregated TARDBP through an evolutionarily conserved mechanism
    • a component
  • part of a protein complex involved in RNA splicing
  • component of the ubiquitin-positive, tau-negative inclusions specific for frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS)
  • TARDBP is physically associated with FMR1 and Staufen (STAU1) to form a functional complex, and depletion of TARDBP/FMR1/STAU1 sensitizes cells to apoptosis and DNA damages
  • PARK2 and TARDBP formed a multiprotein complex with HDAC6, perhaps to mediate TARDBP translocation
    • INTERACTION
    DNA
  • (TG)nTm elements
  • 3'UTR of human low molecular weight, hNFL
  • single-stranded nucleic acids (
  • DNA-binding protein
  • binds specifically to pyrimidine-rich motifs in HIV-1 double-stranded TAR DNA
    • RNA RNA binding
    small molecule
    protein
  • VCP
  • ubiquilin 1, UBQLN
  • histone deacetylase 6, HDAC6
  • FUS/TLS
  • fused in sarcoma/translated in liposarcoma, FUS/TLS
  • ataxin-2, ATXN2
  • Dicer complex, Drosha complex and primary miRNAs
  • TARDBP is physically associated with fragile X mental retardation protein (FMR1) and Staufen (STAU1) to form a functional complex
  • TARDBP/FMR1/STAU1 specifically binds to the 3prime-UTR of SIRT1 mRNA (
  • p62/sequestosome 1, p62/SQSTM1
  • CDC37 is essential for the stability of TARDBP and can be affected by MAPT accumulation
  • TARDBP is cleaved by LGMN in brain
  • RGNE, FUS/TLS and p62
  • Nucleus Accumbens 1, NAC1
  • PARK2 ubiquitinates TARDBP and facilitates its cytosolic accumulation through a multiprotein complex with HDAC6
  • TARDBP leads to activation of GSK3B and GSK3B regulates the VAPB-RMDN3 interaction
  • functional/physical partnership between FMR1 and TARDBP that mechanistically links several neurodevelopmental disorders and neurodegenerative diseases
  • abnormal alternative splicing of ATG4B transcripts in ALS neural tissue in agreement with TARDBP loss of function, leading to impaired autophagy
  • TARDBP regulates expression of the neuronal growth-associated factor STMN2
  • PTK2 UPS impairment via SQSTM1 phosphorylation in TARDBP proteinopathies
  • cytoplasmic mutant TARDBP interacts with proteasome assembly proteins PSMG2, which might lead to the impairment of the proteasomal activity
    • cell & other
  • associates with cytoplasmic stress granules, which are transient structures that form in response to stress
    • REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) ALS10
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --other  
    component of cytoplasmic inclusions in frontotemporal degeneration and amyotrophic lateral sclerosis (aggregation of TARDBP C-terminal fragments, found in cytoplasmic inclusions is regulated by phosphorylation events and both the autophagy and proteasome-mediated degradation pathways)
    constitutional     --over  
    enhancing exon 7 inclusion during the survival of motor neuron pre-mRNA splicing
    constitutional       loss of function
    may induce neuronal degeneration probably through dysregulation of Rho family GTPases
    constitutional       gain of function
    in motor neurons of sporadic ALS patients
    constitutional       gain of function
    in some FTLD-U patients
    constitutional     --other  
    inclusions have been found in Alzheimer's disease (AD) cases, most often in a limbic distribution, with or without hippocampal sclerosis
    Susceptibility
  • to sporadic amyotrophic lateral sclerosis
  • to Ewing sarcoma
    • Variant & Polymorphism SNP , other
  • P363A and A382P missense mutations may predispose to ALS in approximately 2 p100 of the individuals
  • rs9430161 associated with susceptibility to Ewing sarcoma
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neuromuscularlaterale amyotrophy sclerosis 
    TARDBP–ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TARDBP proteinopathies
    neuromuscularneuropathy 
    TARDBP–ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TARDBP proteinopathies
    neurologyneurodegenerative 
    reduced insulin/IGF-1 signaling could ameliorate TARDBP toxicity by decreasing its aggregation in neurons
    neurologyneurodegenerative 
    targeting of TARDBP mitochondrial localization is a promising therapeutic approach for neurodegeneration
    ANIMAL & CELL MODELS
  • postnatal deletion of Tardbp in mice caused dramatic loss of body fat followed by rapid death
  • aberrant Tdp-43- and FUS/TLS-positive nuclear inclusions, abnormal accumulation of mitochondria in motor neurons, immature neuromuscular junctions, and atrophy of skeletal muscle in Tdp-43 mice
  • In SH-SY5Y human neuroblastoma cells, knockdown of TDP-43 caused altered splicing of about 200 transcripts (
  • autophagy activation is an effective route for therapy of Tdp-43 Tg mice with FTLD-U phenotypes