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词条 TARDBP
释义

  1. Function

  2. Clinical significance

  3. References

  4. Further reading

  5. External links

{{Infobox_gene}}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.[5][6]

In spinal motor neurons TDP-43 has also been shown in humans to be a low molecular weight neurofilament (hNFL) mRNA-binding protein.[7] 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.[8]

Recently, it has been demonstrated that zinc ions are able to induce aggregation of endogenous TDP-43 in cells.[9] Moreover, zinc could bind to RNA binding domain of TDP-43 and induce the formation of amyloid-like aggregates in vitro.[10]

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[11]) and in amyotrophic lateral sclerosis (ALS).[12][13] 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.[14] Abnormalities of TDP-43 also occur in an important subset of Alzheimer's disease patients, correlating with clinical and neuropathologic features indexes.[15]

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).[16] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.[17][18][19] Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.[20] The N-terminal domain, which contributes importantly to the aggregation of the C-terminal region, has a novel structure with two negatively charged loops.[21]

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References

1. ^1 {{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 | date = June 1995 | pmid = 7745706 | pmc = 189073 | url = http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=7745706 }}
2. ^{{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 | date = April 2009 | pmid = 19174564 | pmc = 2665213 | doi = 10.1093/nar/gkp013 }}
3. ^[https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23435 Gene Result]
4. ^{{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 = The Journal of Biological Chemistry | volume = 286 | issue = 2 | pages = 1204–15 | date = January 2011 | pmid = 21051541 | pmc = 3020728 | doi = 10.1074/jbc.M110.190884 }}
5. ^{{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 = The Journal of Biological Chemistry | volume = 276 | issue = 39 | pages = 36337–43 | date = September 2001 | pmid = 11470789 | doi = 10.1074/jbc.M104236200 }}
6. ^{{cite journal | vauthors = Mercado PA, Ayala YM, Romano M, Buratti E, Baralle FE | title = Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene | journal = Nucleic Acids Research | volume = 33 | issue = 18 | pages = 6000–10 | date = 2005-10-12 | pmid = 16254078 | pmc = 1270946 | doi = 10.1093/nar/gki897 }}
7. ^{{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 Neurosciences | volume = 35 | issue = 2 | pages = 320–7 | date = June 2007 | pmid = 17481916 | doi = 10.1016/j.mcn.2007.03.007 }}
8. ^{{cite journal | vauthors = Wang IF, Wu LS, Chang HY, Shen CK|authorlink3=Howard Y. Chang | 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 | date = May 2008 | pmid = 18088371 | doi = 10.1111/j.1471-4159.2007.05190.x }}
9. ^{{cite journal | vauthors = Caragounis A, Price KA, Soon CP, Filiz G, Masters CL, Li QX, Crouch PJ, White AR | title = Zinc induces depletion and aggregation of endogenous TDP-43 | journal = Free Radical Biology & Medicine | volume = 48 | issue = 9 | pages = 1152–61 | date = May 2010 | pmid = 20138212 | doi = 10.1016/j.freeradbiomed.2010.01.035 }}
10. ^{{cite journal | vauthors = Garnier C, Devred F, Byrne D, Puppo R, Roman AY, Malesinski S, Golovin AV, Lebrun R, Ninkina NN, Tsvetkov PO | title = Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates | language = En | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 6812 | date = July 2017 | pmid = 28754988 | pmc = 5533730 | doi = 10.1038/s41598-017-07215-7 }}
11. ^{{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 Neuropathologica | volume = 122 | issue = 1 | pages = 111–3 | date = July 2011 | pmid = 21644037 | pmc = 3285143 | doi = 10.1007/s00401-011-0845-8 }}
12. ^{{cite journal | vauthors = Bräuer S, Zimyanin V, Hermann A | title = Prion-like properties of disease-relevant proteins in amyotrophic lateral sclerosis | journal = Journal of Neural Transmission | volume = 125 | issue = 4 | pages = 591–613 | date = April 2018 | pmid = 29417336 | doi = 10.1007/s00702-018-1851-y }}
13. ^{{cite journal | vauthors = Lau DH, Hartopp N, Welsh NJ, Mueller S, Glennon EB, Mórotz GM, Annibali A, Gomez-Suaga P, Stoica R, Paillusson S, Miller CC | title = Disruption of ER-mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis | journal = Cell Death & Disease | volume = 9 | issue = 3 | pages = 327 | date = February 2018 | pmid = 29491392 | pmc = 5832427 | doi = 10.1038/s41419-017-0022-7 }}
14. ^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.
15. ^{{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 = Journal of Neuropathology and Experimental Neurology | volume = 70 | issue = 9 | pages = 788–98 | date = September 2011 | pmid = 21865887 | pmc = 3197017 | doi = 10.1097/nen.0b013e31822c62cf }}
16. ^{{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 | date = July 2007 | pmid = 17492294 | doi = 10.1007/s00401-007-0226-5 }}
17. ^{{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 | date = March 2008 | pmid = 18309045 | doi = 10.1126/science.1154584 }}
18. ^{{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 Suppl 1 | issue = suppl 1 | pages = S35–45 | year = 2013 | pmid = 22751173 | pmc = 3532959 | doi = 10.3233/JAD-2012-129036 }}
19. ^{{cite journal |last1=Babić Leko |first1=M |last2=Župunski |first2=V |last3=Kirincich |first3=J |last4=Smilović |first4=D |last5=Hortobágyi |first5=T |last6=Hof |first6=PR |last7=Šimić |first7=G |title=Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion. |journal=Behavioural neurology |date=2019 |volume=2019 |pages=2909168 |doi=10.1155/2019/2909168 |pmid=30774737}}
20. ^{{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 }}
21. ^.{{cite journal | vauthors = Mompeán M, Romano V, Pantoja-Uceda D, Stuani C, Baralle FE, Buratti E, Laurents DV | title = The TDP-43 N-terminal domain structure at high resolution | journal = The FEBS Journal | volume = 283 | issue = 7 | pages = 1242–60 | date = April 2016 | pmid = 26756435 | doi = 10.1111/febs.13651 | hdl = 10261/162654 }}

Further reading

{{refbegin|35em}}
  • {{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 | date = July 2007 | pmid = 17492294 | doi = 10.1007/s00401-007-0226-5 }}
  • {{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 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
  • {{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 | date = February 1996 | pmid = 8599929 | pmc = 449964 }}
  • {{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 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 }}
  • {{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 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
  • {{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 | date = November 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }}
  • {{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 | date = March 2001 | pmid = 11230166 | pmc = 311072 | doi = 10.1101/gr.GR1547R }}
  • {{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 | date = April 2001 | pmid = 11285240 | pmc = 145463 | doi = 10.1093/emboj/20.7.1774 }}
  • {{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 = The Journal of Biological Chemistry | volume = 276 | issue = 39 | pages = 36337–43 | date = September 2001 | pmid = 11470789 | doi = 10.1074/jbc.M104236200 }}
  • {{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 of the United States of America | volume = 99 | issue = 21 | pages = 13583–8 | date = October 2002 | pmid = 12361981 | pmc = 129717 | doi = 10.1073/pnas.212483099 }}
  • {{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 | date = July 2004 | pmid = 15231747 | pmc = 442147 | doi = 10.1101/gr.2122004 }}
  • {{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 | date = October 2004 | pmid = 15489336 | pmc = 528930 | doi = 10.1101/gr.2576704 }}
  • {{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 = The Journal of Biological Chemistry | volume = 280 | issue = 45 | pages = 37572–84 | date = November 2005 | pmid = 16157593 | doi = 10.1074/jbc.M505557200 }}
  • {{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 | date = September 2005 | pmid = 16169070 | doi = 10.1016/j.cell.2005.08.029 }}
  • {{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 | date = October 2005 | pmid = 16189514 | doi = 10.1038/nature04209 }}
  • {{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 = Database issue | pages = D415–8 | date = January 2006 | pmid = 16381901 | pmc = 1347501 | doi = 10.1093/nar/gkj139 }}
{{refend}}

External links

{{Commons category|TAR DNA-binding protein 43, TDP-43}}
  • [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]
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