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{{Infobox_gene}}
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'''TAR DNA-binding protein 43''' (TDP-43, transactive response DNA binding protein 43&nbsp;[[Atomic mass unit|kDa]]), is a [[protein]] that in humans is encoded by the ''TARDBP'' [[gene]].<ref name="pmid7745706">{{cite journal |vauthors=Ou SH, Wu F, Harrich D, García-Martínez LF, Gaynor RB | title = Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs | journal = Journal of Virology | volume = 69 | issue = 6 | pages = 3584–96 | year = 1995 | pmid = 7745706 | pmc = 189073 | url = http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=7745706 }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image = PBB_Protein_TARDBP_image.jpg
| image_source = [[Protein Data Bank|PDB]] rendering based on 1wf0.
| PDB = {{PDB2|1wf0}}, {{PDB2|2cqg}}
| Name = TAR DNA binding protein
| HGNCid = 11571
| Symbol = TARDBP
| AltSymbols =; TDP-43
| OMIM = 605078
| ECnumber = 
| Homologene = 7221
| MGIid = 2387629
| GeneAtlas_image1 = PBB_GE_TARDBP_221264_s_at_tn.png
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0003723 |text = RNA binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008017 |text = microtubule binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006366 |text = transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0006397 |text = mRNA processing}} {{GNF_GO|id=GO:0007067 |text = mitosis}} {{GNF_GO|id=GO:0008380 |text = RNA splicing}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 23435
    | Hs_Ensembl = ENSG00000120948
    | Hs_RefseqProtein = NP_031401
    | Hs_RefseqmRNA = NM_007375
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 1
    | Hs_GenLoc_start = 10995266
    | Hs_GenLoc_end = 11008133
    | Hs_Uniprot = Q13148
    | Mm_EntrezGene = 230908
    | Mm_Ensembl = ENSMUSG00000041459
    | Mm_RefseqmRNA = NM_001003898
    | Mm_RefseqProtein = NP_001003898
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 4
    | Mm_GenLoc_start = 147456182
    | Mm_GenLoc_end = 147470796
    | Mm_Uniprot = Q3U591
  }}
}}
'''TAR DNA binding protein''', also known as '''TARDBP''' or as '''TDP-43''', is a [[cellular]] [[protein]].<ref>[http://www.ncbi.nlm.nih.gov/pubmed/7745706 Cloning and characterization of a novel cellular p...[J Virol. 1995&#93; - PubMed Result<!-- Bot generated title -->]</ref> It is one of the [[genes]] on [[chromosome 1]]. Pathology in this protein has been linked to a couple of diseases, such as frontotemporal lobar degeneration and motor neuron disease.<ref>[http://www.ncbi.nlm.nih.gov/pubmed/17492294 TDP-43 proteinopathy: the neuropathology underlyin...[Acta Neuropathol. 2007&#93; - PubMed Result<!-- Bot generated title -->]</ref>


===TARDBP and HIV===  
TDP-43 is a transcriptional [[repressor]] that binds to chromosomally integrated TAR DNA and represses [[HIV-1]] transcription. In addition, this protein regulates alternate splicing of the [[Cystic fibrosis transmembrane conductance regulator|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.<ref name="doi10.1093/nar/gkp013">{{cite journal |vauthors=Kuo PH, Doudeva LG, Wang YT, Shen CK, Yuan HS | title = Structural insights into TDP-43 in nucleic-acid binding and domain interactions | journal = Nucleic Acids Research | volume = 37 | issue = 6 | pages = 1799–808 | year = 2009 | pmid = 19174564 | pmc = 2665213 | doi = 10.1093/nar/gkp013 }}</ref> A similar pseudogene is present on chromosome 20.<ref>[https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23435 Gene Result<!-- Bot generated title -->]</ref>
[[HIV]]-1, the causative agent of [[AIDS|acquired immunodeficiency syndrome]] (AIDS), contains an [[RNA]] [[genome]] that produces a chromosomally integrated [[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 of the transcription initiation site. The protein encoded by this gene is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. A similar pseudogene is present on chromosome 20.<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23435 Gene Result<!-- Bot generated title -->]</ref>
 
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.<ref>{{cite journal |vauthors=Sephton CF, Cenik C, Kucukural A, Dammer EB, Cenik B, Han Y, Dewey CM, Roth FP, Herz J, Peng J, Moore MJ, Yu G | title = Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes. | journal = J Biol Chem | volume = 286 | issue = 2 | pages = 1204–15 | year = 2011 | pmid = 21051541 | doi = 10.1074/jbc.M110.190884 | pmc=3020728}}</ref>
 
TDP-43 was originally identified as a transcriptional repressor that binds to chromosomally integrated [[Trans-activation response element (TAR)|trans-activation response element]] (TAR) DNA and represses [[HIV-1]] transcription.<ref name="pmid7745706"/> It was also reported to regulate alternate splicing of the [[CFTR (gene)|CFTR]] gene and the [[APOA2|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.<ref>{{cite journal |vauthors=Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C, Shoesmith C | title = TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein | journal = Molecular and Cellular Neuroscience | volume = 35 | issue = 2 | pages = 320–7 | year = 2007 | pmid = 17481916 | doi = 10.1016/j.mcn.2007.03.007 }}</ref> It has also shown to be a [[neuronal activity response factor]] in the dendrites of hippocampal neurons suggesting possible roles in regulating mRNA stability, transport and local translation in neurons.<ref>{{cite journal |vauthors=Wang IF, Wu LS, Chang HY, Shen CK | title = TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor | journal = Journal of Neurochemistry | volume = 105 | issue = 3 | pages = 797–806 | year = 2008 | pmid = 18088371 | doi = 10.1111/j.1471-4159.2007.05190.x }}</ref>
 
Recently, it has been demonstrated that zinc ions are able to induce aggregation of endogenous TDP-43 in cells.<ref>{{Cite journal|last=Caragounis|first=Aphrodite|last2=Price|first2=Katherine Ann|last3=Soon|first3=Cynthia P.W.|last4=Filiz|first4=Gulay|last5=Masters|first5=Colin L.|last6=Li|first6=Qiao-Xin|last7=Crouch|first7=Peter J.|last8=White|first8=Anthony R.|title=Zinc induces depletion and aggregation of endogenous TDP-43|url=http://linkinghub.elsevier.com/retrieve/pii/S0891584910000687|journal=Free Radical Biology and Medicine|volume=48|issue=9|pages=1152–1161|doi=10.1016/j.freeradbiomed.2010.01.035}}</ref> Moreover, zinc could bind to RNA binding domain of TDP-43 and induce the formation of amyloid-like aggregates ''in vitro.''<ref>{{Cite journal|last=Garnier|first=Cyrille|last2=Devred|first2=François|last3=Byrne|first3=Deborah|last4=Puppo|first4=Rémy|last5=Roman|first5=Andrei Yu.|last6=Malesinski|first6=Soazig|last7=Golovin|first7=Andrey V.|last8=Lebrun|first8=Régine|last9=Ninkina|first9=Natalia N.|date=2017-07-28|title=Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates|url=https://www.nature.com/articles/s41598-017-07215-7|journal=Scientific Reports|language=En|volume=7|issue=1|doi=10.1038/s41598-017-07215-7|issn=2045-2322}}</ref>
 
== Clinical significance ==
 
A hyper-[[phosphorylation|phosphorylated]], [[ubiquitin]]ated 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<ref name="pmid21644037">{{cite journal |vauthors=Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM | title = A harmonized classification system for FTLD-TDP pathology | journal = Acta Neuropathol. | volume = 122 | issue = 1 | pages = 111–3 |date=July 2011 | pmid = 21644037 | pmc = 3285143 | doi = 10.1007/s00401-011-0845-8  }}</ref>) and in [[Amyotrophic lateral sclerosis]] (ALS).<ref name="pmid17023659">{{cite journal |vauthors=Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM | title = Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis | journal = Science | volume = 314 | issue = 5796 | pages = 130–3 | year = 2006 | pmid = 17023659 | doi = 10.1126/science.1134108  }}</ref> Elevated levels of the TDP-43 protein have also been identified in individuals diagnosed with [[chronic traumatic encephalopathy]], a condition that often mimics ALS and that has been associated with athletes who have experienced multiple [[concussion]]s and other types of [[head injury]].<ref>[[Alan Schwarz|Schwarz, Alan]]. [https://www.nytimes.com/2010/08/18/sports/18gehrig.html "Study Says Brain Trauma Can Mimic A.L.S."], ''[[The New York Times]]'', August 18, 2010. Accessed August 18, 2010.</ref> Abnormalities of TDP-43 also occur in an important subset of [[Alzheimer's disease]] patients,  correlating with clinical and neuropathologic features indexes.<ref name="pmid21865887">{{cite journal |vauthors=Tremblay C, St-Amour I, Schneider J, Bennett DA, Calon F | title = Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease. | journal = J Neuropathol Exp Neurol. | volume = 70 | issue = 9 | pages = 788–98|date=2011 | pmid = 21865887| doi=10.1097/nen.0b013e31822c62cf | pmc=3197017}}</ref>
 
[[HIV]]-1, the causative agent of [[AIDS|acquired immunodeficiency syndrome]] (AIDS), contains an [[RNA]] [[genome]] that produces a chromosomally integrated [[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 [[frontotemporal lobar degeneration]] and [[amyotrophic lateral sclerosis]] (ALS).<ref name="pmid17492294">{{cite journal |vauthors=Kwong LK, Neumann M, Sampathu DM, Lee VM, Trojanowski JQ | title = TDP-43 proteinopathy: The neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease | journal = Acta Neuropathologica | volume = 114 | issue = 1 | pages = 63–70 | year = 2007 | pmid = 17492294 | doi = 10.1007/s00401-007-0226-5 }}</ref> In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.<ref>{{cite journal |vauthors=Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE | title = TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis | journal = Science | volume = 319 | issue = 5870 | pages = 1668–72 | year = 2008 | pmid = 18309045 | doi = 10.1126/science.1154584 }}</ref><ref>{{cite journal |vauthors=Gendron TF, Rademakers R, Petrucelli L | title = TARDBP mutation analysis in TDP-43 proteinopathies and deciphering the toxicity of mutant TDP-43 | journal = [[Journal of Alzheimer's Disease]] | volume = 33 | issue = suppl&nbsp;1 | pages = S35-S45 | year = 2013 | pmid = 22751173 | pmc = 3532959 | doi=10.3233/JAD-2012-129036}}</ref>  Cytoplasmic TDP-43 pathology is the dominant histopathological feature of [[multisystem proteinopathy]].<ref name="pmid23455423">{{cite journal |vauthors=Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP | title = Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS | journal = Nature | volume = 495 | issue = 7442 | pages = 467–73 |date=March 2013 | pmid = 23455423 | pmc = 3756911 | doi = 10.1038/nature11922  }}</ref> The N-terminal domain, which contributes importantly to the aggregation of the C-terminal region, has a novel structure with two negatively charged loops.<ref>.{{Cite journal|title = The TDP-43 N-Terminal Domain Structure at High Resolution|url = http://onlinelibrary.wiley.com/doi/10.1111/febs.13651/abstract|journal = FEBS Journal|date = 2016-01-01|issn = 1742-4658|pages = 1242–1260|doi = 10.1111/febs.13651|language = en|first = Miguel|last = Mompean|first2 = Valentina|last2 = Romano|first3 = David|last3 = Pantoja-Uceda|first4 = Cristiana|last4 = Stuani|first5 = Francisco E.|last5 = Baralle|first6 = Emanuele|last6 = Buratti|first7 = Douglas V.|last7 = Laurents|volume=283}}</ref>
{{Clear}}


==References==
==References==
{{reflist|2}}
{{reflist|35em}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin|35em}}
{{PBB_Further_reading
*{{cite journal |vauthors=Kwong LK, Neumann M, Sampathu DM, Lee VM, Trojanowski JQ | title = TDP-43 proteinopathy: The neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease | journal = Acta Neuropathologica | volume = 114 | issue = 1 | pages = 63–70 | year = 2007 | pmid = 17492294 | doi = 10.1007/s00401-007-0226-5 }}
| citations =
*{{cite journal |vauthors=Maruyama K, Sugano S | title = Oligo-capping: A simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | year = 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
*{{cite journal | author=Kwong LK, Neumann M, Sampathu DM, ''et al.'' |title=TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease. |journal=Acta Neuropathol. |volume=114 |issue= 1 |pages= 63-70 |year= 2007 |pmid= 17492294 |doi= 10.1007/s00401-007-0226-5 }}
*{{cite journal |vauthors=Tokai N, Fujimoto-Nishiyama A, Toyoshima Y, Yonemura S, Tsukita S, Inoue J, Yamamota T | title = Kid, a novel kinesin-like DNA binding protein, is localized to chromosomes and ''the mitotic'' spindle | journal = The EMBO Journal | volume = 15 | issue = 3 | pages = 457–67 | year = 1996 | pmid = 8599929 | pmc = 449964 }}
*{{cite journal | author=Ou SH, Wu F, Harrich D, ''et al.'' |title=Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. |journal=J. Virol. |volume=69 |issue= 6 |pages= 3584-96 |year= 1995 |pmid= 7745706 |doi=  }}
*{{cite journal |vauthors=Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: Two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | year = 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 }}
*{{cite journal  | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171-4 |year= 1994 |pmid= 8125298 |doi= }}
*{{cite journal |vauthors=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5′-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | year = 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
*{{cite journal | author=Tokai N, Fujimoto-Nishiyama A, Toyoshima Y, ''et al.'' |title=Kid, a novel kinesin-like DNA binding protein, is localized to chromosomes and the mitotic spindle. |journal=EMBO J. |volume=15 |issue= 3 |pages= 457-67 |year= 1996 |pmid= 8599929 |doi= }}
*{{cite journal |vauthors=Hartley JL, Temple GF, Brasch MA | title = DNA Cloning Using in Vitro Site-Specific Recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–95 | year = 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }}
*{{cite journal | author=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery. |journal=Genome Res. |volume=6 |issue= 9 |pages= 791-806 |year= 1997 |pmid= 8889548 |doi= }}
*{{cite journal |vauthors=Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A | title = Toward a Catalog of Human Genes and Proteins: Sequencing and Analysis of 500 Novel Complete Protein Coding Human cDNAs | journal = Genome Research | volume = 11 | issue = 3 | pages = 422–35 | year = 2001 | pmid = 11230166 | pmc = 311072 | doi = 10.1101/gr.GR1547R }}
*{{cite journal | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149-56 |year= 1997 |pmid= 9373149 |doi= }}
*{{cite journal |vauthors=Buratti E, Dörk T, Zuccato E, Pagani F, Romano M, Baralle FE | title = Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping | journal = The EMBO Journal | volume = 20 | issue = 7 | pages = 1774–84 | year = 2001 | pmid = 11285240 | pmc = 145463 | doi = 10.1093/emboj/20.7.1774 }}
*{{cite journal | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788-95 |year= 2001 |pmid= 11076863 |doi= }}
*{{cite journal |vauthors=Buratti E, Baralle FE | title = Characterization and Functional Implications of the RNA Binding Properties of Nuclear Factor TDP-43, a Novel Splicing Regulator of CFTR Exon 9 | journal = Journal of Biological Chemistry | volume = 276 | issue = 39 | pages = 36337–43 | year = 2001 | pmid = 11470789 | doi = 10.1074/jbc.M104236200 }}
*{{cite journal | author=Wiemann S, Weil B, Wellenreuther R, ''et al.'' |title=Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs. |journal=Genome Res. |volume=11 |issue= 3 |pages= 422-35 |year= 2001 |pmid= 11230166 |doi= 10.1101/gr.154701 }}
*{{cite journal |vauthors=Wang IF, Reddy NM, Shen CK | title = Higher order arrangement of the eukaryotic nuclear bodies | journal = Proceedings of the National Academy of Sciences | volume = 99 | issue = 21 | pages = 13583–8 | year = 2002 | pmid = 12361981 | doi = 10.1073/pnas.212483099 | pmc=129717}}
*{{cite journal | author=Buratti E, Dörk T, Zuccato E, ''et al.'' |title=Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. |journal=EMBO J. |volume=20 |issue= 7 |pages= 1774-84 |year= 2001 |pmid= 11285240 |doi= 10.1093/emboj/20.7.1774 }}
*{{cite journal |vauthors=Lehner B, Sanderson CM | title = A Protein Interaction Framework for Human mRNA Degradation | journal = Genome Research | volume = 14 | issue = 7 | pages = 1315–23 | year = 2004 | pmid = 15231747 | pmc = 442147 | doi = 10.1101/gr.2122004 }}
*{{cite journal | author=Buratti E, Baralle FE |title=Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. |journal=J. Biol. Chem. |volume=276 |issue= 39 |pages= 36337-43 |year= 2001 |pmid= 11470789 |doi= 10.1074/jbc.M104236200 }}
*{{cite journal |vauthors=Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A | title = From ORFeome to Biology: A Functional Genomics Pipeline | journal = Genome Research | volume = 14 | issue = 10b | pages = 2136–44 | year = 2004 | pmid = 15489336 | pmc = 528930 | doi = 10.1101/gr.2576704 }}
*{{cite journal | author=Wang IF, Reddy NM, Shen CK |title=Higher order arrangement of the eukaryotic nuclear bodies. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 21 |pages= 13583-8 |year= 2002 |pmid= 12361981 |doi= 10.1073/pnas.212483099 }}
*{{cite journal |vauthors=Buratti E, Brindisi A, Giombi M, Tisminetzky S, Ayala YM, Baralle FE | title = TDP-43 Binds Heterogeneous Nuclear Ribonucleoprotein A/B through Its C-terminal Tail: AN IMPORTANT REGION FOR THE INHIBITION OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR EXON 9 SPLICING | journal = Journal of Biological Chemistry | volume = 280 | issue = 45 | pages = 37572–84 | year = 2005 | pmid = 16157593 | doi = 10.1074/jbc.M505557200 }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal |vauthors=Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE | title = A Human Protein-Protein Interaction Network: A Resource for Annotating the Proteome | journal = Cell | volume = 122 | issue = 6 | pages = 957–68 | year = 2005 | pmid = 16169070 | doi = 10.1016/j.cell.2005.08.029 }}
*{{cite journal | author=Lehner B, Sanderson CM |title=A protein interaction framework for human mRNA degradation. |journal=Genome Res. |volume=14 |issue= 7 |pages= 1315-23 |year= 2004 |pmid= 15231747 |doi= 10.1101/gr.2122004 }}
*{{cite journal |vauthors=Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein–protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | year = 2005 | pmid = 16189514 | doi = 10.1038/nature04209 }}
*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal |vauthors=Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S | title = The LIFEdb database in 2006 | journal = Nucleic Acids Research | volume = 34 | issue = 90001 | pages = D415 | year = 2006 | pmid = 16381901 | pmc = 1347501 | doi = 10.1093/nar/gkj139 }}
*{{cite journal | author=Wiemann S, Arlt D, Huber W, ''et al.'' |title=From ORFeome to biology: a functional genomics pipeline. |journal=Genome Res. |volume=14 |issue= 10B |pages= 2136-44 |year= 2004 |pmid= 15489336 |doi= 10.1101/gr.2576704 }}
*{{cite journal | author=Buratti E, Brindisi A, Giombi M, ''et al.'' |title=TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing. |journal=J. Biol. Chem. |volume=280 |issue= 45 |pages= 37572-84 |year= 2006 |pmid= 16157593 |doi= 10.1074/jbc.M505557200 }}
*{{cite journal | author=Stelzl U, Worm U, Lalowski M, ''et al.'' |title=A human protein-protein interaction network: a resource for annotating the proteome. |journal=Cell |volume=122 |issue= 6 |pages= 957-68 |year= 2005 |pmid= 16169070 |doi= 10.1016/j.cell.2005.08.029 }}
*{{cite journal | author=Rual JF, Venkatesan K, Hao T, ''et al.'' |title=Towards a proteome-scale map of the human protein-protein interaction network. |journal=Nature |volume=437 |issue= 7062 |pages= 1173-8 |year= 2005 |pmid= 16189514 |doi= 10.1038/nature04209 }}
*{{cite journal | author=Mehrle A, Rosenfelder H, Schupp I, ''et al.'' |title=The LIFEdb database in 2006. |journal=Nucleic Acids Res. |volume=34 |issue= Database issue |pages= D415-8 |year= 2006 |pmid= 16381901 |doi= 10.1093/nar/gkj139 }}
*{{cite journal  | author=Gregory SG, Barlow KF, McLay KE, ''et al.'' |title=The DNA sequence and biological annotation of human chromosome 1. |journal=Nature |volume=441 |issue= 7091 |pages= 315-21 |year= 2006 |pmid= 16710414 |doi= 10.1038/nature04727 }}
}}
{{refend}}
{{refend}}


{{protein-stub}}
==External links==
{{Uncategorize|date=May 2008}}
{{Commons category|TAR DNA-binding protein 43, TDP-43}}
{{WikiDoc Sources}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=tardbp-als  GeneReviews/NCBI/NIH/UW entry on TARDBP-Related Amyotrophic Lateral Sclerosis]
 
{{PDB Gallery|geneid=23435}}

Revision as of 21:57, 29 November 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa), is a protein that in humans is encoded by the TARDBP gene.[1]

Function

TDP-43 is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses 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.[2] A similar pseudogene is present on chromosome 20.[3]

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.[4]

TDP-43 was originally identified as a transcriptional repressor that binds to chromosomally integrated trans-activation response element (TAR) DNA and represses HIV-1 transcription.[1] 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.[5] It has also shown to be a neuronal activity response factor in the dendrites of hippocampal neurons suggesting possible roles in regulating mRNA stability, transport and local translation in neurons.[6]

Recently, it has been demonstrated that zinc ions are able to induce aggregation of endogenous TDP-43 in cells.[7] Moreover, zinc could bind to RNA binding domain of TDP-43 and induce the formation of amyloid-like aggregates in vitro.[8]

Clinical significance

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[9]) and in Amyotrophic lateral sclerosis (ALS).[10] Elevated levels of the TDP-43 protein have also been identified in individuals diagnosed with chronic traumatic encephalopathy, a condition that often mimics ALS and that has been associated with athletes who have experienced multiple concussions and other types of head injury.[11] Abnormalities of TDP-43 also occur in an important subset of Alzheimer's disease patients, correlating with clinical and neuropathologic features indexes.[12]

HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated 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 frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS).[13] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.[14][15] Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.[16] The N-terminal domain, which contributes importantly to the aggregation of the C-terminal region, has a novel structure with two negatively charged loops.[17]

References

  1. ↑ 1.0 1.1 Ou SH, Wu F, Harrich D, García-Martínez LF, Gaynor RB (1995). "Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs". Journal of Virology. 69 (6): 3584–96. PMC 189073. PMID 7745706.
  2. ↑ Kuo PH, Doudeva LG, Wang YT, Shen CK, Yuan HS (2009). "Structural insights into TDP-43 in nucleic-acid binding and domain interactions". Nucleic Acids Research. 37 (6): 1799–808. doi:10.1093/nar/gkp013. PMC 2665213. PMID 19174564.
  3. ↑ Gene Result
  4. ↑ Sephton CF, Cenik C, Kucukural A, Dammer EB, Cenik B, Han Y, Dewey CM, Roth FP, Herz J, Peng J, Moore MJ, Yu G (2011). "Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes". J Biol Chem. 286 (2): 1204–15. doi:10.1074/jbc.M110.190884. PMC 3020728. PMID 21051541.
  5. ↑ Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C, Shoesmith C (2007). "TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein". Molecular and Cellular Neuroscience. 35 (2): 320–7. doi:10.1016/j.mcn.2007.03.007. PMID 17481916.
  6. ↑ Wang IF, Wu LS, Chang HY, Shen CK (2008). "TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor". Journal of Neurochemistry. 105 (3): 797–806. doi:10.1111/j.1471-4159.2007.05190.x. PMID 18088371.
  7. ↑ Caragounis, Aphrodite; Price, Katherine Ann; Soon, Cynthia P.W.; Filiz, Gulay; Masters, Colin L.; Li, Qiao-Xin; Crouch, Peter J.; White, Anthony R. "Zinc induces depletion and aggregation of endogenous TDP-43". Free Radical Biology and Medicine. 48 (9): 1152–1161. doi:10.1016/j.freeradbiomed.2010.01.035.
  8. ↑ Garnier, Cyrille; Devred, François; Byrne, Deborah; Puppo, Rémy; Roman, Andrei Yu.; Malesinski, Soazig; Golovin, Andrey V.; Lebrun, Régine; Ninkina, Natalia N. (2017-07-28). "Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates". Scientific Reports. 7 (1). doi:10.1038/s41598-017-07215-7. ISSN 2045-2322.
  9. ↑ Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM (July 2011). "A harmonized classification system for FTLD-TDP pathology". Acta Neuropathol. 122 (1): 111–3. doi:10.1007/s00401-011-0845-8. PMC 3285143. PMID 21644037.
  10. ↑ Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006). "Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis". Science. 314 (5796): 130–3. doi:10.1126/science.1134108. PMID 17023659.
  11. ↑ Schwarz, Alan. "Study Says Brain Trauma Can Mimic A.L.S.", The New York Times, August 18, 2010. Accessed August 18, 2010.
  12. ↑ Tremblay C, St-Amour I, Schneider J, Bennett DA, Calon F (2011). "Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease". J Neuropathol Exp Neurol. 70 (9): 788–98. doi:10.1097/nen.0b013e31822c62cf. PMC 3197017. PMID 21865887.
  13. ↑ Kwong LK, Neumann M, Sampathu DM, Lee VM, Trojanowski JQ (2007). "TDP-43 proteinopathy: The neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease". Acta Neuropathologica. 114 (1): 63–70. doi:10.1007/s00401-007-0226-5. PMID 17492294.
  14. ↑ Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE (2008). "TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis". Science. 319 (5870): 1668–72. doi:10.1126/science.1154584. PMID 18309045.
  15. ↑ Gendron TF, Rademakers R, Petrucelli L (2013). "TARDBP mutation analysis in TDP-43 proteinopathies and deciphering the toxicity of mutant TDP-43". Journal of Alzheimer's Disease. 33 (suppl&nbsp, 1): S35–S45. doi:10.3233/JAD-2012-129036. PMC 3532959. PMID 22751173.
  16. ↑ Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP (March 2013). "Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS". Nature. 495 (7442): 467–73. doi:10.1038/nature11922. PMC 3756911. PMID 23455423.
  17. ↑ .Mompean, Miguel; Romano, Valentina; Pantoja-Uceda, David; Stuani, Cristiana; Baralle, Francisco E.; Buratti, Emanuele; Laurents, Douglas V. (2016-01-01). "The TDP-43 N-Terminal Domain Structure at High Resolution". FEBS Journal. 283: 1242–1260. doi:10.1111/febs.13651. ISSN 1742-4658.

Further reading

External links

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