TAR DNA-binding protein 43

{{Short description|Protein found in humans}} {{Infobox gene}} '''Transactive response DNA binding protein 43 kDa''' ('''TAR DNA-binding protein 43''' or '''TDP-43''') is a protein that in humans is encoded by the ''TARDBP'' gene.<ref name="pmid7745706">{{cite journal |author5-link=Richard Gaynor | 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 = 3584–3596 | date = June 1995 | pmid = 7745706 | pmc = 189073 | doi = 10.1128/JVI.69.6.3584-3596.1995 }}</ref>

== Structure == TDP-43 is 414 amino acid residues long. It consists of four 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;<ref name="pmid28663553">{{cite journal | vauthors = Afroz T, Hock EM, Ernst P, Foglieni C, Jambeau M, Gilhespy LA, Laferriere F, Maniecka Z, Plückthun A, Mittl P, Paganetti P, Allain FH, Polymenidou M | display-authors = 6 | title = Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation | journal = Nature Communications | volume = 8 | issue = 1 | article-number = 45 | date = June 2017 | pmid = 28663553 | pmc = 5491494 | doi = 10.1038/s41467-017-00062-0 | bibcode = 2017NatCo...8...45A }}</ref><ref name="pmid29438978">{{cite journal | vauthors = Wang A, Conicella AE, Schmidt HB, Martin EW, Rhoads SN, Reeb AN, Nourse A, Ramirez Montero D, Ryan VH, Rohatgi R, Shewmaker F, Naik MT, Mittag T, Ayala YM, Fawzi NL | display-authors = 6 | title = A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing | journal = The EMBO Journal | volume = 37 | issue = 5 | article-number = e97452 | date = March 2018 | pmid = 29438978 | pmc = 5830921 | doi = 10.15252/embj.201797452 }}</ref> two highly conserved folded RNA recognition motifs spanning residues 106–176 (RRM1) and 191–259 (RRM2), respectively, required to bind target RNA and DNA;<ref name="pmid24240615">{{cite journal | vauthors = Alcalde AI, Barcina Y, Larralde J, Ilundain A | title = Role of calcium in the phloretin effects on sugar transport in rat small intestine | journal = Revista Espanola de Fisiologia | volume = 42 | issue = 1 | pages = 23–28 | date = March 1986 | pmid = 2424061 | doi = 10.1038/nsmb.2698 | s2cid = 13783277 }}</ref> 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.<ref name="pmid27545621">{{cite journal | vauthors = Conicella AE, Zerze GH, Mittal J, Fawzi NL | title = ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain | journal = Structure | volume = 24 | issue = 9 | pages = 1537–1549 | date = September 2016 | pmid = 27545621 | pmc = 5014597 | doi = 10.1016/j.str.2016.07.007 }}</ref>

The entire protein devoid of large solubilising tags has been purified.<ref name="pmid31287959">{{cite journal | vauthors = Vivoli Vega M, Nigro A, Luti S, Capitini C, Fani G, Gonnelli L, Boscaro F, Chiti F | display-authors = 6 | title = Isolation and characterization of soluble human full-length TDP-43 associated with neurodegeneration | journal = FASEB Journal | volume = 33 | issue = 10 | pages = 10780–10793 | date = October 2019 | pmid = 31287959 | doi = 10.1096/fj.201900474R | doi-access = free }}</ref> The full-length protein is a dimer.<ref name="pmid31287959"/> The dimer is formed due to a self-interaction between two NTD domains,<ref name="pmid28663553"/><ref name="pmid29438978"/> where the dimerisation can be propagated to form higher-order oligomers.<ref name="pmid28663553"/>

The protein sequence also has a nuclear localization signal (NLS, residues 82–98), a former nuclear export signal (NES residues 239–250) and 3 putative caspase-3 cleavage sites (residues 13, 89, 219).<ref name="pmid31287959"/>

In December 2021 the structure of TDP-43 was resolved with cryo-EM<ref>{{cite journal | vauthors = Arseni D, Hasegawa M, Murzin AG, Kametani F, Arai M, Yoshida M, Ryskeldi-Falcon B | title = Structure of pathological TDP-43 filaments from ALS with FTLD | journal = Nature | volume = 601 | issue = 7891 | pages = 139–143 | date = January 2022 | pmid = 34880495 | pmc = 7612255 | doi = 10.1038/s41586-021-04199-3 | bibcode = 2022Natur.601..139A }}</ref><ref>{{Cite web |title=An ALS Protein, Revealed |url=https://www.science.org/content/blog-post/als-protein-revealed |access-date=2022-04-04 |website=www.science.org |language=en}}</ref> but shortly after it was argued that in the context of FTLD-TDP the protein involved could be TMEM106B (which has been also resolved with cryo-EM), rather than of TDP-43.<ref>{{cite journal | vauthors = Jiang YX, Cao Q, Sawaya MR, Abskharon R, Ge P, DeTure M, Dickson DW, Fu JY, Ogorzalek Loo RR, Loo JA, Eisenberg DS | display-authors = 6 | title = Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B not TDP-43 | journal = Nature | pages = 304–309 | date = March 2022 | volume = 605 | issue = 7909 | pmid = 35344984 | doi = 10.1038/s41586-022-04670-9 | s2cid = 247777613 | pmc = 9844993 | bibcode = 2022Natur.605..304J }}</ref><ref>{{Cite web |title=Frontotemporal Dementia: Not the Protein We Thought |url=https://www.science.org/content/blog-post/frontotemporal-dementia-not-protein-we-thought |access-date=2022-04-04 |website=www.science.org |language=en}}</ref>

=== N-Terminal domain (NTD) ===

The NTD located between residues 1 and 76 is involved in TDP-43 polymerization.<ref name="Qin 18619–18624">{{cite journal | vauthors = Qin H, Lim LZ, Wei Y, Song J | title = TDP-43 N terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium that can be shifted by binding to ssDNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 52 | pages = 18619–18624 | date = December 2014 | pmid = 25503365 | pmc = 4284588 | doi = 10.1073/pnas.1413994112 | bibcode = 2014PNAS..11118619Q | doi-access = free }}</ref> Indeed, dimers are formed by head-to-head interactions between NTDs, and the polymer thus obtained allows for pre-mRNA splicing.<ref name="Prasad_2019">{{cite journal | vauthors = Prasad A, Bharathi V, Sivalingam V, Girdhar A, Patel BK | title = Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis | journal = Frontiers in Molecular Neuroscience | volume = 12 | article-number = 25 | date = 2019-02-14 | pmid = 30837838 | pmc = 6382748 | doi = 10.3389/fnmol.2019.00025 | doi-access = free }}</ref> However, further oligomerization brings to more toxic accumulates. This process of polymerization into dimers, larger forms or just stabilizing monomers is dependent on TDP-43 conformational equilibrium between monomers, homodimers and oligomers. Hence, in TDP-43 diseased cells, TDP-43's over-expression leads to the NTD showing high propensity to aggregate. Contrary to this, in normal cells, normal levels of TDP-43 allow for folded NTD, preventing aggregates and polymers formation.

More recently, this domain was found to have a ubiquitin-like structure. It bears 27,6% of homology with Ubiquitin-1 and a β1-β2-α1-β3-β4-β5-β6 + 2*SO42- form.<ref>{{Cite web|title=TARDBP TAR DNA binding protein [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/23435|access-date=2021-12-13|website=www.ncbi.nlm.nih.gov}}</ref> Ubiquitin-like domain are usually associated with a greater affinity for RNA/DNA. However, in the unique case of TDP-43, the Ubiquitin-like NTD binds directly to ssDNA. This interaction permits the conformational equilibrium cited higher to shift towards non-aggregated forms.<ref>{{cite journal | vauthors = Qin H, Lim LZ, Wei Y, Song J | title = TDP-43 N terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium that can be shifted by binding to ssDNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 52 | pages = 18619–18624 | date = December 2014 | pmid = 25503365 | doi = 10.1073/pnas.1413994112 | pmc = 4284588 | bibcode = 2014PNAS..11118619Q | doi-access = free }}</ref>

The domain spanning from [1,80] has a solenoid-like structure which sterically impedes interactions between aggregation prone C-term regions.<ref name="Prasad_2019" />

All of this raises the possibility that NTD and the RNA recognition motifs (later on defined) could cooperatively interact with nucleic acids to accomplish TDP-43's physiological functions.<ref name = "Ratti_2016">{{cite journal | vauthors = Ratti A, Buratti E | title = Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins | journal = Journal of Neurochemistry | volume = 138 | issue = Suppl 1 | pages = 95–111 | date = August 2016 | pmid = 27015757 | doi = 10.1111/jnc.13625 | s2cid = 12679353 | doi-access = free }}</ref>

=== Mitochondrial localization signal ===

There are six mitochondrial localization signals<ref>{{cite journal | vauthors = Huang C, Yan S, Zhang Z | title = Maintaining the balance of TDP-43, mitochondria, and autophagy: a promising therapeutic strategy for neurodegenerative diseases | journal = Translational Neurodegeneration | volume = 9 | issue = 1 | article-number = 40 | date = October 2020 | pmid = 33126923 | pmc = 7597011 | doi = 10.1186/s40035-020-00219-w | doi-access = free }}</ref> to be accounted on TDP-43's amino acid sequence, although only M1, M3, and M5 were shown to be essential for mitochondrial localization. Indeed, their ablation leads to a lessened mitochondrial localization.

These localizing sequences are found on the following amino acids:

M1: [35, 41], M2: [105, 112], M3: [146-150], M4: [228, 235], M5: [294, 300], M6: [228, 236].

=== Nuclear localization signal (NLS) === The nuclear localization signal (NLS) domain is located between residues 82 and 98 is of critical importance in ALS, and such is witnessed by the depletion or the mutations (notably A90V) of this domain, which cause loss-of-function from nucleus and promote aggregating, two processes very likely to conduct to TDP-43's toxic gain of function.<ref name="Prasad_2019" />

It is thereby of the utmost importance to note that TDP-43's nuclear localization is absolutely critical for it to fulfill its physiological functions.<ref name = "Ratti_2016" />

=== RNA recognition motif === The RNA recognition motif ranges between residues 105 and 181, much like many hnRNPs, TDP-43's RRMs encompass highly conserved motifs of primary importance for fulfilling their function. Both RRMs follow this pattern: β1-α1-β2-β3-α2-β4-β5,<ref name="Prasad_2019" /> which allows them to bind to both RNA and DNA onto U G/T G-repeats of 3'UTR (Untranslated Terminal Regions) end of mRNA/DNA.<ref name="Qin 18619–18624"/>

These sequences mainly ensure mRNA processing, RNA export and RNA stabilizing. It is notably thanks to these sequences that TDP-43 importantly binds to its own mRNA regulates its very own solubility and polymerization.

=== RRM2 === RRM2 spans between residues 181 and 261. In pathological conditions, it notably binds to p65/NF-kB, an apoptosis implicated factor, and is thus a potential therapeutic target. Moreover it can be burdened with a mutation, D169G, altering a key cleaving site for regulating formation of toxic inclusions.<ref>{{cite journal | vauthors = Pozzi S, Thammisetty SS, Codron P, Rahimian R, Plourde KV, Soucy G, Bareil C, Phaneuf D, Kriz J, Gravel C, Julien JP | display-authors = 6 | title = Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology | journal = The Journal of Clinical Investigation | volume = 129 | issue = 4 | pages = 1581–1595 | date = February 2019 | pmid = 30667370 | doi = 10.1172/JCI123931 |pmc=6436898 }}</ref>

=== Nuclear export signal (NES) === The nuclear export signal is located between residues 239 and 251 sequence probably bears a role in TDP-43's shuttling function, and was recently found using a prediction algorithm.<ref name="Strong_2007">{{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 = 320–327 | date = June 2007 | pmid = 17481916 | doi = 10.1016/j.mcn.2007.03.007 | s2cid = 42553015 }}</ref>

=== Disordered glycin rich C-terminal domain (CTD) === The Disordered Glycin Rich C-terminal domain is located between residues 277 and 414. Much like 70 other RNA binding proteins, TDP-43 bears a Q/N rich domain [344, 366] which resembles yeast prion sequence. This sequence is called a Prion-Like Domain (PLD).<ref>{{cite journal | vauthors = Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T, Yoshida M, Murayama S, Mann DM, Akiyama H, Hasegawa M | display-authors = 6 | title = Prion-like properties of pathological TDP-43 aggregates from diseased brains | journal = Cell Reports | volume = 4 | issue = 1 | pages = 124–134 | date = July 2013 | pmid = 23831027 | doi = 10.1016/j.celrep.2013.06.007 | doi-access = free }}</ref>

PLDs are low complexity sequences that have been reported to mediate gene regulation via Liquid-Liquid Phase Transition (LLP) thus driving RNP granule assembly.<ref name="Prasad_2019" /> Forming these microscopically visible RNP granules is thought to induce more effective gene regulatory process.<ref>{{cite book | vauthors = Fan AC, Leung AK | title = RNA Processing | chapter = RNA Granules and Diseases: A Case Study of Stress Granules in ALS and FTLD | series = Advances in Experimental Medicine and Biology | volume = 907 | pages = 263–296 | date = 2016 | pmid = 27256390 | pmc = 5247449 | doi = 10.1007/978-3-319-29073-7_11 | publisher = Springer International Publishing | isbn = 978-3-319-29071-3 | veditors = Yeo GW | place = Cham }}</ref>

It is here noted that LLP are reversible phenomenons of de-mixing a solution into two distinct liquid phases, hereby forming granules.

Mutations within the TDP-43 proteins Glycine Rich Region (GRR) have recently been identified as associates that can contribute to various neurodegenerative diseases, with the most notable and common NDD being ALS, about 10% of the mutations causing familial ALS are accredited with the TDP-43 protein <ref>{{cite journal | vauthors = Suk TR, Rousseaux MW | title = The role of TDP-43 mislocalization in amyotrophic lateral sclerosis | journal = Molecular Neurodegeneration | volume = 15 | issue = 1 | article-number = 45 | date = August 2020 | pmid = 32799899 | pmc = 7429473 | doi = 10.1186/s13024-020-00397-1 | s2cid = 221129473 | doi-access = free }}</ref>

This CTD is often reported to play important role in pathogenic behavior of TDP-43:

RNPs granules could have a role in stress response, and thus, aging, or persistence stress could lead the LLPs to turn into irreversible Liquid Solid Phase separation, pathological aggregates notably found in ALS neurons.<ref>{{cite journal | vauthors = Hennig S, Kong G, Mannen T, Sadowska A, Kobelke S, Blythe A, Knott GJ, Iyer KS, Ho D, Newcombe EA, Hosoki K, Goshima N, Kawaguchi T, Hatters D, Trinkle-Mulcahy L, Hirose T, Bond CS, Fox AH | display-authors = 6 | title = Prion-like domains in RNA binding proteins are essential for building subnuclear paraspeckles | journal = The Journal of Cell Biology | volume = 210 | issue = 4 | pages = 529–539 | date = August 2015 | pmid = 26283796 | pmc = 4539981 | doi = 10.1083/jcb.201504117 }}</ref>

The CTD's disorganized structure can turn into a full fledged amyloid-like beta-sheet rich structure, causing it to adopt prion-like properties.<ref name="Prasad_2019" />

Moreover, CTFs are a common marker in diseased neurons and are argued to be of high toxicity.

However, notice is to be taken that some points are not always consensual. Indeed, due to its hydrophobic structure, TDP-43 can be hard to analyze, and parts of it remain somewhat vague. Precise sites of phosphorylation, methylation, or even binding are still a bit elusive.<ref name="Prasad_2019" />

== 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.<ref>{{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 = 1774–1784 | date = April 2001 | pmid = 11285240 | pmc = 145463 | doi = 10.1093/emboj/20.7.1774 }}</ref><ref name="doi10.1093/nar/gkp013">{{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 = 1799–1808 | date = April 2009 | pmid = 19174564 | pmc = 2665213 | doi = 10.1093/nar/gkp013 }}</ref> A similar pseudogene is present on chromosome 20.<ref>[https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=23435 Gene Result]</ref>

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.<ref>{{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 | display-authors = 6 | title = Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes | journal = The Journal of Biological Chemistry | volume = 286 | issue = 2 | pages = 1204–1215 | date = January 2011 | pmid = 21051541 | pmc = 3020728 | doi = 10.1074/jbc.M110.190884 | doi-access = free }}</ref>

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.<ref name="pmid7745706"/> It was also reported to regulate alternate splicing of the CFTR gene and the apoA-II gene.<ref>{{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 = 36337–36343 | date = September 2001 | pmid = 11470789 | doi = 10.1074/jbc.M104236200 | doi-access = free }}</ref>

In spinal motor neurons TDP-43 has also been shown in humans to be a low molecular weight neurofilament (hNFL) mRNA-binding protein.<ref name="Strong_2007"/> 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.<ref>{{cite journal | vauthors = Wang IF, Wu LS, Chang HY, Shen CK | 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 | s2cid = 41139555 | author-link3 = Howard Y. Chang | doi-access = free }}</ref>

It has been demonstrated that zinc ions are able to induce aggregation of endogenous TDP-43 in cells.<ref>{{cite journal | vauthors = Caragounis A, Price KA, Soon CP, Filiz G, Masters CL, Li QX, Crouch PJ, White AR | display-authors = 6 | title = Zinc induces depletion and aggregation of endogenous TDP-43 | journal = Free Radical Biology & Medicine | volume = 48 | issue = 9 | pages = 1152–1161 | date = May 2010 | pmid = 20138212 | doi = 10.1016/j.freeradbiomed.2010.01.035 }}</ref> Moreover, zinc could bind to RNA binding domain of TDP-43 and induce the formation of amyloid-like aggregates ''in vitro.''<ref>{{cite journal | vauthors = Garnier C, Devred F, Byrne D, Puppo R, Roman AY, Malesinski S, Golovin AV, Lebrun R, Ninkina NN, Tsvetkov PO | display-authors = 6 | 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 | article-number = 6812 | date = July 2017 | pmid = 28754988 | pmc = 5533730 | doi = 10.1038/s41598-017-07215-7 | bibcode = 2017NatSR...7.6812G }}</ref> Consistently, Zn2+ binds a short peptide (residues 256–264) from the C-terminus of TDP-43's RRM2 domain with an association constant of ~1.6×105 M−1, supporting a specific Zn2+ site that may regulate nucleic-acid binding.<ref>{{cite journal | vauthors = Golovin AV, Devred F, Yatoui D, Roman AY, Zalevsky AO, Puppo R, Lebrun R, Guerlesquin F, Tsvetkov PO | title = Zinc Binds to RRM2 Peptide of TDP-43 | journal = International Journal of Molecular Sciences | year = 2020 | volume = 21 | issue = 23 | page = 9080 | doi = 10.3390/ijms21239080 | doi-access = free | pmc = 7730363 }}</ref>

===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.<ref name =Mitra2019>{{cite journal | vauthors = Mitra J, Guerrero EN, Hegde PM, Liachko NF, Wang H, Vasquez V, Gao J, Pandey A, Taylor JP, Kraemer BC, Wu P, Boldogh I, Garruto RM, Mitra S, Rao KS, Hegde ML | display-authors = 6 | title = Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 10 | pages = 4696–4705 | date = March 2019 | pmid = 30770445 | pmc = 6410842 | doi = 10.1073/pnas.1818415116 | bibcode = 2019PNAS..116.4696M | doi-access = free }}</ref> 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.<ref name=Mitra2019/>

== 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<ref name="pmid21644037">{{cite journal | vauthors = Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM | display-authors = 6 | title = A harmonized classification system for FTLD-TDP pathology | journal = Acta Neuropathologica | volume = 122 | issue = 1 | pages = 111–113 | date = July 2011 | pmid = 21644037 | pmc = 3285143 | doi = 10.1007/s00401-011-0845-8 }}</ref>) and in amyotrophic lateral sclerosis (ALS).<ref>{{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 | s2cid = 3895544 }}</ref><ref>{{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 | display-authors = 6 | title = Disruption of ER-mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis | journal = Cell Death & Disease | volume = 9 | issue = 3 | page = 327 | date = February 2018 | pmid = 29491392 | pmc = 5832427 | doi = 10.1038/s41419-017-0022-7 }}</ref> 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).<ref>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.</ref> Abnormalities of TDP-43 also occur in an important subset of Alzheimer's disease patients, correlating with clinical and neuropathologic features indexes.<ref name="pmid21865887">{{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 = 788–798 | date = September 2011 | pmid = 21865887 | pmc = 3197017 | doi = 10.1097/nen.0b013e31822c62cf }}</ref> 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. New monoclonal antibodies, 2G11 and 2H1, have been developed to specify different TDP-43 inclusion types that occur across neurodegenerative diseases, without relying on hyper-phosphorylated epitopes.<ref name = "Trejo-Lopez_2020">{{cite journal | vauthors = Trejo-Lopez JA, Sorrentino ZA, Riffe CJ, Lloyd GM, Labuzan SA, Dickson DW, Yachnis AT, Prokop S, Giasson BI | display-authors = 6 | title = Novel monoclonal antibodies targeting the RRM2 domain of human TDP-43 protein | journal = Neuroscience Letters | volume = 738 | article-number = 135353 | date = November 2020 | pmid = 32905837 | pmc = 7924408 | doi = 10.1016/j.neulet.2020.135353 }}</ref> These antibodies were raised against an epitope within the RRM2 domain (amino acid residues 198–216).<ref name = "Trejo-Lopez_2020" />

Mutations in the ''TARDBP'' gene are associated with neurodegenerative disorders including frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS).<ref name="pmid17492294">{{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 | s2cid = 20773388 }}</ref> In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.<ref>{{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 | display-authors = 6 | title = TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis | journal = Science | volume = 319 | issue = 5870 | pages = 1668–1672 | date = March 2008 | pmid = 18309045 | pmc = 7116650 | doi = 10.1126/science.1154584 | s2cid = 28744172 | bibcode = 2008Sci...319.1668S }}</ref><ref>{{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 | issue = Suppl 1 | pages = S35–S45 | year = 2013 | pmid = 22751173 | pmc = 3532959 | doi = 10.3233/JAD-2012-129036 }}</ref><ref name="Leko">{{cite journal | vauthors = Babić Leko M, Župunski V, Kirincich J, Smilović D, Hortobágyi T, Hof PR, Šimić G | title = Molecular Mechanisms of Neurodegeneration Related to ''C9orf72'' Hexanucleotide Repeat Expansion | journal = Behavioural Neurology | volume = 2019 | issue = | article-number = 2909168 | date = 2019 | pmid = 30774737 | pmc = 6350563 | doi = 10.1155/2019/2909168 | doi-access = free }}</ref> While the aberrant mislocalization and cytoplasmic aggregation of TDP-43 characterizes FTLD with TDP-43 pathology (FTLD-TDP), recent work suggests the amyloid fibrils found in human FTLD-TDP brains are composed of transmembrane lysosomal protein TMEM106b rather than TDP-43.<ref>{{cite journal | vauthors = Jiang YX, Cao Q, Sawaya MR, Abskharon R, Ge P, DeTure M, Dickson DW, Fu JY, Ogorzalek Loo RR, Loo JA, Eisenberg DS | display-authors = 6 | title = Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43 | journal = Nature | volume = 605 | issue = 7909 | pages = 304–309 | date = May 2022 | pmid = 35344984 | doi = 10.1038/s41586-022-04670-9 | pmc = 9844993 | bibcode = 2022Natur.605..304J }}</ref> Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.<ref name="pmid23455423">{{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 | display-authors = 6 | title = Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS | journal = Nature | volume = 495 | issue = 7442 | pages = 467–473 | date = March 2013 | pmid = 23455423 | pmc = 3756911 | doi = 10.1038/nature11922 | bibcode = 2013Natur.495..467K }}</ref> The N-terminal domain, which contributes importantly to the aggregation of the C-terminal region, has a novel structure with two negatively charged loops.<ref>.{{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 = 1242–1260 | date = April 2016 | pmid = 26756435 | doi = 10.1111/febs.13651 | doi-access = free | hdl = 10261/162654 | hdl-access = free }}</ref> 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.<ref name="pmid29943193">{{cite journal | vauthors = Svahn AJ, Don EK, Badrock AP, Cole NJ, Graeber MB, Yerbury JJ, Chung R, Morsch M | display-authors = 6 | title = Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons | journal = Acta Neuropathologica | volume = 136 | issue = 3 | pages = 445–459 | date = September 2018 | pmid = 29943193 | pmc = 6096729 | doi = 10.1007/s00401-018-1875-2 }}</ref> {{Clear}}

==Figures== 750px|thumb|center|(A) Structure of TAR DNA-binding protein 43 (TDP-43) protein. The TDP-43 protein contains 414 amino acids and consists of an N-terminal region with a nuclear localisation signal (NLS). In addition, the protein consists of two RNA recognition motifs (RRM1 and RRM2), a nuclear export signal (NES) and a C-terminal domain with a glutamine/asparagine-rich (Q/N) and glycine-rich regions. Mitochondrial localisation motifs (M1; M3; M5) are also evident. Pathogenic mutations are predominantly located within the C-terminal region which can exhibit prion-like properties. The numbers represent amino acid lengths. (B) The TDP-43 protein is critical for mediating RNA metabolism. In the nucleus, TDP-43 is important for transcription and splicing of messenger RNA (mRNA), as well as maintaining RNA stability (pA) and transport to nucleus. In addition, TDP-43 regulates biogenesis of microRNA (miRNA) and processing of long non-coding RNA (lncRNA). Although predominantly located within the nucleus, TDP-43 shuttles between the nucleus and the cytoplasm. In the cytoplasm, TDP-43 participates in mRNA stability, translation, formation of stress and ribonucleoprotein (RNP) transport granules. From a review by de Boer et al., 2020.<ref name="pmid33177049">{{cite journal | vauthors = de Boer EM, Orie VK, Williams T, Baker MR, De Oliveira HM, Polvikoski T, Silsby M, Menon P, van den Bos M, Halliday GM, van den Berg LH, Van Den Bosch L, van Damme P, Kiernan MC, van Es MA, Vucic S | title = TDP-43 proteinopathies: a new wave of neurodegenerative diseases | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 92| issue = 1| pages = 86–95| date = November 2020 | pmid = 33177049 | pmc = 7803890 | doi = 10.1136/jnnp-2020-322983 | url = }}</ref>

== References == {{reflist|35em}}

== 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 | s2cid = 20773388 }} * {{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 = 171–174 | 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 = 457–467 | date = February 1996 | pmid = 8599929 | pmc = 449964 | doi = 10.1002/j.1460-2075.1996.tb00378.x }} * {{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 | doi-access = free }} * {{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 = 149–156 | 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 = 1788–1795 | 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 | display-authors = 6 | 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 = 422–435 | 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 = 1774–1784 | 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 = 36337–36343 | date = September 2001 | pmid = 11470789 | doi = 10.1074/jbc.M104236200 | doi-access = free }} * {{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 = 13583–13588 | date = October 2002 | pmid = 12361981 | pmc = 129717 | doi = 10.1073/pnas.212483099 | doi-access = free | bibcode = 2002PNAS...9913583W }} * {{cite journal | vauthors = Lehner B, Sanderson CM | title = A protein interaction framework for human mRNA degradation | journal = Genome Research | volume = 14 | issue = 7 | pages = 1315–1323 | 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 | display-authors = 6 | title = From ORFeome to biology: a functional genomics pipeline | journal = Genome Research | volume = 14 | issue = 10B | pages = 2136–2144 | 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 = 37572–37584 | date = November 2005 | pmid = 16157593 | doi = 10.1074/jbc.M505557200 | doi-access = free }} * {{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 | display-authors = 6 | title = A human protein-protein interaction network: a resource for annotating the proteome | journal = Cell | volume = 122 | issue = 6 | pages = 957–968 | date = September 2005 | pmid = 16169070 | doi = 10.1016/j.cell.2005.08.029 | hdl-access = free | s2cid = 8235923 | hdl = 11858/00-001M-0000-0010-8592-0 }} * {{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 | display-authors = 6 | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–1178 | date = October 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | s2cid = 4427026 | bibcode = 2005Natur.437.1173R }} * {{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 | display-authors = 6 | title = The LIFEdb database in 2006 | journal = Nucleic Acids Research | volume = 34 | issue = Database issue | pages = D415–D418 | 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/books/NBK5942/ GeneReviews/NCBI/NIH/UW entry on TARDBP-Related Amyotrophic Lateral Sclerosis] * {{PDBe-KB2|Q13148|TAR DNA-binding protein 43}}

Category:DNA-binding proteins