TARDBP

TAR DNA binding protein

PDB rendering based on 1wf0.
Identifiers
Symbols TARDBP; ALS10; TDP-43
External IDs OMIM: 605078 MGI: 2387629 HomoloGene: 7221 GeneCards: TARDBP Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 23435 230908
Ensembl ENSG00000120948 ENSMUSG00000041459
UniProt Q13148 Q3U591
RefSeq (mRNA) NM_007375 NM_001003898
RefSeq (protein) NP_031401 NP_001003898
Location (UCSC) Chr 1:
11.07 – 11.09 Mb		 Chr 4:
147.99 – 148 Mb
PubMed search [1] [2]

TAR DNA-binding protein 43 (TDP-43), is a cellular protein which in humans is encoded by the TARDBP gene.[1]

Contents

Discovery

TARDBP was originally identified as a transcriptional repressor that binds to chromosomally integrated 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. Later it was discovered that hyper-phosphorylated, ubiquitinated and cleaved form of TARDBP, known as pathologic TDP43, is the major disease protein in ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal dementia (FTLD-U) and in Amyotrophic lateral sclerosis (ALS).[2] 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.[3]

Clinical significance

TDP-43 has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation.

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 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. 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.[4] A similar pseudogene is present on chromosome 20.[5] In spinal motor neurons TDP-43 has also been shown to be a human low molecular weight microfilament (hNFL) mRNA-binding protein.[6] 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.[7]

Mutations in the TARDBP gene are associated with neurodegenerative disorders including frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS).[8] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.[9] TDP-43 is not present in the brain tissue of patients with schizophrenia.[10]

Zinc induces depletion and aggregation of endogenous TDP-43.[11]

External Links

References

  1. ^ a b 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. http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=7745706. 
  2. ^ Neumann, M.; Sampathu, D. M.; Kwong, L. K.; Truax, A. C.; Micsenyi, M. C.; Chou, T. T.; Bruce, J.; Schuck, T. et al. (2006). "Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis". Science 314 (5796): 130–3. doi:10.1126/science.1134108. PMID 17023659. 
  3. ^ Schwarz, Alan. "Study Says Brain Trauma Can Mimic A.L.S.", The New York Times, August 18, 2010. Accessed August 18, 2010.
  4. ^ Kuo, P.-H.; Doudeva, L. G.; Wang, Y.-T.; Shen, C.-K. J.; Yuan, H. S. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2665213. 
  5. ^ Gene Result
  6. ^ Strong, Michael J.; Volkening, Kathryn; Hammond, Robert; Yang, Wencheng; Strong, Wendy; Leystra-Lantz, Cheryl; Shoesmith, Christen (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. 
  7. ^ Wang, I.-Fan; Wu, Lien-Szn; Chang, Hsiang-Yu; Shen, C.-K. James (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. 
  8. ^ Kwong, Linda K.; Neumann, Manuela; Sampathu, Deepak M.; Lee, Virginia M.-Y.; Trojanowski, John Q. (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. 
  9. ^ Sreedharan, J.; Blair, I. P.; Tripathi, V. B.; Hu, X.; Vance, C.; Rogelj, B.; Ackerley, S.; Durnall, J. C. et al. (2008). "TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis". Science 319 (5870): 1668–72. doi:10.1126/science.1154584. PMID 18309045. 
  10. ^ Mateen, Farrah J.; Josephs, Keith A. (2009). "TDP-43 is not present in brain tissue of patients with schizophrenia". Schizophrenia Research 108 (1–3): 297–8. doi:10.1016/j.schres.2008.08.033. PMID 18829261. 
  11. ^ Caragounis, Aphrodite; Price, Katherine Ann; Soon, Cynthia P.W.; Filiz, Gulay; Masters, Colin L.; Li, Qiao-Xin; Crouch, Peter J.; White, Anthony R. (2010). "Zinc induces depletion and aggregation of endogenous TDP-43". Free Radical Biology and Medicine 48 (9): 1152–61. doi:10.1016/j.freeradbiomed.2010.01.035. PMID 20138212. 

Further reading