TARDBP

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TAR DNA binding protein
Protein TARDBP PDB 1wf0.png
2nd RRM motif of TDP-43. PDB rendering based on 1wf0.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols TARDBP ; ALS10; TDP-43
External IDs OMIM605078 MGI2387629 HomoloGene7221 GeneCards: TARDBP Gene
RNA expression pattern
PBB GE TARDBP 221264 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 23435 230908
Ensembl ENSG00000120948 ENSMUSG00000041459
UniProt Q13148 Q921F2
RefSeq (mRNA) NM_007375 NM_001003898
RefSeq (protein) NP_031401 NP_001003898
Location (UCSC) Chr 1:
11.07 – 11.09 Mb
Chr 4:
148.61 – 148.63 Mb
PubMed search [1] [2]

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[edit]

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.

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.[4] 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.[5]

Clinical significance[edit]

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[6]) and in Amyotrophic lateral sclerosis (ALS).[7] 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.[8]

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).[9] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.[10][11] Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.[12]

References[edit]

  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. 
  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. ^ 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. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ Schwarz, Alan. "Study Says Brain Trauma Can Mimic A.L.S.", The New York Times, August 18, 2010. Accessed August 18, 2010.
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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 1): S35–S45. PMC 3532959. PMID 22751173. 
  12. ^ 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. 

Further reading[edit]

External links[edit]