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TARDBP  -  TAR DNA binding protein

Homo sapiens

 
 
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Disease relevance of TARDBP

 

High impact information on TARDBP

  • Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping [7].
  • Taken together, our results demonstrate that 5'-GTGTGT motifs on the complementary strand are required to prevent premature expression of SP-10 during spermatogenesis and implicate TDP-43 as the putative regulatory factor [8].
  • Further, Northern analysis and immunohistochemistry of mouse testis showed the presence of TDP-43 in cell-types where the SP-10 gene remains repressed [8].
  • TDP43 from C.elegans lacks the glycine-rich domain found at the carboxy terminus of the other two homologues [9].
  • Notable among the proteins identified were the cytoskeletal cytokeratins, RNA helicases, oxidant-antioxidant enzymes, the TAR DNA binding protein (a protein that associates with nuclear domain 10 [ND10] structures), and heat shock protein 70- and 60-kDa isoforms (Hsp70 and Hsp60, respectively) [10].
 

Biological context of TARDBP

  • Significantly, blocking of TDP-43 expression by small interfering RNA overrides the need for all the other cis-acting elements making exon 3 inclusion constitutive even in the presence of disrupted exonic and intronic enhancers [11].
  • Although TDP-43 bound strongly to double-stranded TAR DNA via its ribonucleoprotein protein-binding motifs, it did not bind to TAR RNA extending from +1 to +80 [1].
  • Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance [12].
  • We report that depletion of TDP43 through RNA interference removes splicing inhibition caused by unfavorable (UG)mU(n) sequences, indicating that TDP43 exerts a potent inhibitory effect in vivo [13].
  • Dephosphorylation treatment of the sarkosyl insoluble fraction has shown that abnormal phosphorylation takes place in accumulated TDP-43 [2].
 

Anatomical context of TARDBP

 

Psychiatry related information on TARDBP

  • Despite significant clinical, genetic, and neuropathological heterogeneity of FTLD-U, TDP-43 is a common pathological substrate underlying a large subset of these disorders, thereby implicating TDP-43 in novel and unifying mechanisms of FTLD pathogenesis [14].
 

Associations of TARDBP with chemical compounds

 

Physical interactions of TARDBP

  • We have also found that the (GU) repeats in the apoA-II context bind the splicing factor TDP-43 and interfere with exon 3 definition [11].
  • We have recently identified nuclear factor TDP-43 as a novel splicing regulator capable of binding to this element in the CFTR pre-mRNA and inhibiting recognition of the neighboring exon [15].
 

Other interactions of TARDBP

  • Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene [11].
  • Overexpression of UBQLN recruited TDP-43 to detergent-resistant cytoplasmic aggregates that colocalized with the autophagosomal marker, LC3 [16].
 

Analytical, diagnostic and therapeutic context of TARDBP

  • In this study we report the dissection of the RNA binding properties of TDP-43 and their functional implications in relationship with the splicing process [15].
  • Antibody to TDP-43 was used in gel retardation assays to demonstrate that endogenous TDP-43, present in HeLa nuclear extract, also bound to TAR DNA [1].

References

  1. Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. Ou, S.H., Wu, F., Harrich, D., García-Martínez, L.F., Gaynor, R.B. J. Virol. (1995) [Pubmed]
  2. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D., Tsuchiya, K., Yoshida, M., Hashizume, Y., Oda, T. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  3. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neumann, M., Sampathu, D.M., Kwong, L.K., Truax, A.C., Micsenyi, M.C., Chou, T.T., Bruce, J., Schuck, T., Grossman, M., Clark, C.M., McCluskey, L.F., Miller, B.L., Masliah, E., Mackenzie, I.R., Feldman, H., Feiden, W., Kretzschmar, H.A., Trojanowski, J.Q., Lee, V.M. Science (2006) [Pubmed]
  4. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Van Deerlin, V.M., Leverenz, J.B., Bekris, L.M., Bird, T.D., Yuan, W., Elman, L.B., Clay, D., Wood, E.M., Chen-Plotkin, A.S., Martinez-Lage, M., Steinbart, E., McCluskey, L., Grossman, M., Neumann, M., Wu, I.L., Yang, W.S., Kalb, R., Galasko, D.R., Montine, T.J., Trojanowski, J.Q., Lee, V.M., Schellenberg, G.D., Yu, C.E. Lancet. Neurol (2008) [Pubmed]
  5. Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies. Igaz, L.M., Kwong, L.K., Chen-Plotkin, A., Winton, M.J., Unger, T.L., Xu, Y., Neumann, M., Trojanowski, J.Q., Lee, V.M. J. Biol. Chem. (2009) [Pubmed]
  6. An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Guo, W., Chen, Y., Zhou, X., Kar, A., Ray, P., Chen, X., Rao, E.J., Yang, M., Ye, H., Zhu, L., Liu, J., Xu, M., Yang, Y., Wang, C., Zhang, D., Bigio, E.H., Mesulam, M., Shen, Y., Xu, Q., Fushimi, K., Wu, J.Y. Nat. Struct. Mol. Biol. (2011) [Pubmed]
  7. Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. Buratti, E., Dörk, T., Zuccato, E., Pagani, F., Romano, M., Baralle, F.E. EMBO J. (2001) [Pubmed]
  8. cis-requirement for the maintenance of round spermatid-specific transcription. Acharya, K.K., Govind, C.K., Shore, A.N., Stoler, M.H., Reddi, P.P. Dev. Biol. (2006) [Pubmed]
  9. Human, Drosophila, and C.elegans TDP43: nucleic acid binding properties and splicing regulatory function. Ayala, Y.M., Pantano, S., D'Ambrogio, A., Buratti, E., Brindisi, A., Marchetti, C., Romano, M., Baralle, F.E. J. Mol. Biol. (2005) [Pubmed]
  10. Nuclear heat shock response and novel nuclear domain 10 reorganization in respiratory syncytial virus-infected a549 cells identified by high-resolution two-dimensional gel electrophoresis. Brasier, A.R., Spratt, H., Wu, Z., Boldogh, I., Zhang, Y., Garofalo, R.P., Casola, A., Pashmi, J., Haag, A., Luxon, B., Kurosky, A. J. Virol. (2004) [Pubmed]
  11. Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene. Mercado, P.A., Ayala, Y.M., Romano, M., Buratti, E., Baralle, F.E. Nucleic Acids Res. (2005) [Pubmed]
  12. Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance. Buratti, E., Brindisi, A., Pagani, F., Baralle, F.E. Am. J. Hum. Genet. (2004) [Pubmed]
  13. TDP43 depletion rescues aberrant CFTR exon 9 skipping. Ayala, Y.M., Pagani, F., Baralle, F.E. FEBS Lett. (2006) [Pubmed]
  14. TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Cairns, N.J., Neumann, M., Bigio, E.H., Holm, I.E., Troost, D., Hatanpaa, K.J., Foong, C., White, C.L., Schneider, J.A., Kretzschmar, H.A., Carter, D., Taylor-Reinwald, L., Paulsmeyer, K., Strider, J., Gitcho, M., Goate, A.M., Morris, J.C., Mishra, M., Kwong, L.K., Stieber, A., Xu, Y., Forman, M.S., Trojanowski, J.Q., Lee, V.M., Mackenzie, I.R. Am. J. Pathol. (2007) [Pubmed]
  15. Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. Buratti, E., Baralle, F.E. J. Biol. Chem. (2001) [Pubmed]
  16. Potentiation of amyotrophic lateral sclerosis (ALS)-associated TDP-43 aggregation by the proteasome-targeting factor, ubiquilin 1. Kim, S.H., Shi, Y., Hanson, K.A., Williams, L.M., Sakasai, R., Bowler, M.J., Tibbetts, R.S. J. Biol. Chem. (2009) [Pubmed]
 
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