Biology:TARDBP

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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]

Structure

TDP-43 is 414 amino acid residues long. It consists of 4 domains: an N-terminal domain spanning residues 1-76 (NTD) with a well-defined fold that has been shown to form a dimer or oligomer;[2][3] 2 highly conserved folded RNA recognition motifs spanning residues 106-176 (RRM1) and 191-259 (RRM2), respectively, required to bind target RNA and DNA;[4] an unstructured C-terminal domain encompassing residues 274-414 (CTD), which contains a glycine-rich region, is involved in protein-protein interactions, and harbors most of the mutations associated with familial amyotrophic lateral sclerosis.[5]

The entire protein devoid of large solubilising tags has been recently purified.[6] The full-length protein is a dimer.[6] The dimer is formed due to a self-interaction between two NTD domains,[2][3] where the dimerisation can be propagated to form higher-order oligomers.[2]

The protein sequence also has a nuclear localization signal (NLS, residues 82–98), a nuclear export signal (NES residues 239–250) and 3 putative caspase-3 cleavage sites (residues 13, 89, 219).[6]

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.[7] A similar pseudogene is present on chromosome 20.[8]

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.[9]

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.[10][11]

In spinal motor neurons TDP-43 has also been shown in humans to be a low molecular weight neurofilament (hNFL) mRNA-binding protein.[12] 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.[13]

Recently, it has been demonstrated that zinc ions are able to induce aggregation of endogenous TDP-43 in cells.[14] Moreover, zinc could bind to RNA binding domain of TDP-43 and induce the formation of amyloid-like aggregates in vitro.[15]

DNA repair

TDP-43 protein is a key element of the non-homologous end joining (NHEJ) enzymatic pathway that repairs DNA double-strand breaks (DSBs) in pluripotent stem cell-derived motor neurons.[16] TDP-43 is rapidly recruited to DSBs where it acts as a scaffold for the further recruitment of the XRCC4-DNA ligase protein complex that then acts to seal the DNA breaks. In TDP-43 depleted human neural stem cell-derived motor neurons, as well as in sporadic ALS patients’ spinal cord specimens there is significant DSB accumulation and reduced levels of NHEJ.[16]

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[17]) and in amyotrophic lateral sclerosis (ALS).[18][19] Elevated levels of the TDP-43 protein have also been identified in individuals diagnosed with chronic traumatic encephalopathy, and has also been associated with ALS leading to the inference that athletes who have experienced multiple concussions and other types of head injury are at an increased risk for both encephalopathy and motor neuron disease (ALS).[20] Abnormalities of TDP-43 also occur in an important subset of Alzheimer's disease patients, correlating with clinical and neuropathologic features indexes.[21] Misfolded TDP-43 is found in the brains of older adults over age 85 with limbic-predominant age-related TDP-43 encephalopathy, (LATE), a form of dementia.

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).[22] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.[23][24][25] Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.[26] The N-terminal domain, which contributes importantly to the aggregation of the C-terminal region, has a novel structure with two negatively charged loops.[27] A recent study has demonstrated that cellular stress can trigger the abnormal cytoplasmic mislocalisation of TDP-43 in spinal motor neurons in vivo, providing insight into how TDP-43 pathology may develop in sporadic ALS patients.[28]

References

  1. ↑ 1.0 1.1 "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. June 1995. PMID 7745706. PMC 189073. http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=7745706. 
  2. ↑ 2.0 2.1 2.2 "Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation". Nature Communications 8: 45. June 2017. doi:10.1038/s41467-017-00062-0. PMID 28663553. 
  3. ↑ 3.0 3.1 "A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing". EMBO Journal 37: e97452. March 1, 2018. doi:10.15252/embj.201797452. PMID 29438978. 
  4. ↑ "Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43". Nature Struct Mol Biol 20: 1443. December 2013. doi:10.1038/nsmb.2698. PMID 2424061. 
  5. ↑ "ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain". Structure 24: 1537-49. 6 September 2016. doi:10.1016/j.str.2016.07.007. PMID 27545621. 
  6. ↑ 6.0 6.1 6.2 "Isolation and characterization of soluble human full-length TDP-43 associated with neurodegeneration". FASEB J 33: 10780-93. October 2019. doi:10.1096/fj.201900474R. PMID 31287959. 
  7. ↑ "Structural insights into TDP-43 in nucleic-acid binding and domain interactions". Nucleic Acids Research 37 (6): 1799–808. April 2009. doi:10.1093/nar/gkp013. PMID 19174564. 
  8. ↑ Gene Result
  9. ↑ "Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes". The Journal of Biological Chemistry 286 (2): 1204–15. January 2011. doi:10.1074/jbc.M110.190884. PMID 21051541. 
  10. ↑ "Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9". The Journal of Biological Chemistry 276 (39): 36337–43. September 2001. doi:10.1074/jbc.M104236200. PMID 11470789. 
  11. ↑ "Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene". Nucleic Acids Research 33 (18): 6000–10. 2005-10-12. doi:10.1093/nar/gki897. PMID 16254078. 
  12. ↑ "TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein". Molecular and Cellular Neurosciences 35 (2): 320–7. June 2007. doi:10.1016/j.mcn.2007.03.007. PMID 17481916. 
  13. ↑ "TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor". Journal of Neurochemistry 105 (3): 797–806. May 2008. doi:10.1111/j.1471-4159.2007.05190.x. PMID 18088371. 
  14. ↑ "Zinc induces depletion and aggregation of endogenous TDP-43". Free Radical Biology & Medicine 48 (9): 1152–61. May 2010. doi:10.1016/j.freeradbiomed.2010.01.035. PMID 20138212. 
  15. ↑ "Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates" (in En). Scientific Reports 7 (1): 6812. July 2017. doi:10.1038/s41598-017-07215-7. PMID 28754988. Bibcode: 2017NatSR...7.6812G. 
  16. ↑ 16.0 16.1 "Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects". Proc Natl Acad Sci U S A 116: 4696–4705. 2019. doi:10.1073/pnas.1818415116. PMID 30770445. 
  17. ↑ "A harmonized classification system for FTLD-TDP pathology". Acta Neuropathologica 122 (1): 111–3. July 2011. doi:10.1007/s00401-011-0845-8. PMID 21644037. 
  18. ↑ "Prion-like properties of disease-relevant proteins in amyotrophic lateral sclerosis". Journal of Neural Transmission 125 (4): 591–613. April 2018. doi:10.1007/s00702-018-1851-y. PMID 29417336. 
  19. ↑ "Disruption of ER-mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis". Cell Death & Disease 9 (3): 327. February 2018. doi:10.1038/s41419-017-0022-7. PMID 29491392. 
  20. ↑ Schwarz, Alan. "Study Says Brain Trauma Can Mimic A.L.S.", The New York Times , August 18, 2010. Accessed August 18, 2010.
  21. ↑ "Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease". Journal of Neuropathology and Experimental Neurology 70 (9): 788–98. September 2011. doi:10.1097/nen.0b013e31822c62cf. PMID 21865887. 
  22. ↑ "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. July 2007. doi:10.1007/s00401-007-0226-5. PMID 17492294. 
  23. ↑ "TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis". Science 319 (5870): 1668–72. March 2008. doi:10.1126/science.1154584. PMID 18309045. Bibcode: 2008Sci...319.1668S. 
  24. ↑ "TARDBP mutation analysis in TDP-43 proteinopathies and deciphering the toxicity of mutant TDP-43". Journal of Alzheimer's Disease 33 Suppl 1 (suppl 1): S35–45. 2013. doi:10.3233/JAD-2012-129036. PMID 22751173. 
  25. ↑ Babić Leko, M; Župunski, V; Kirincich, J; Smilović, D; Hortobágyi, T; Hof, PR; Šimić, G (2019). "Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion.". Behavioural Neurology 2019: 2909168. doi:10.1155/2019/2909168. PMID 30774737. 
  26. ↑ "Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS". Nature 495 (7442): 467–73. March 2013. doi:10.1038/nature11922. PMID 23455423. Bibcode: 2013Natur.495..467K. 
  27. ↑ ."The TDP-43 N-terminal domain structure at high resolution". The FEBS Journal 283 (7): 1242–60. April 2016. doi:10.1111/febs.13651. PMID 26756435. 
  28. ↑ "Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons.". Acta Neuropathologica 136 (3): 445–459. September 2018. doi:10.1007/s00401-018-1875-2. PMID 29943193. PMC 6096729. https://ro.uow.edu.au/cgi/viewcontent.cgi?article=1098&context=smhpapers1. 

Further reading

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