| Structural highlights
Disease
[TADBP_HUMAN] Defects in TARDBP are the cause of amyotrophic lateral sclerosis type 10 (ALS10) [MIM:612069]. ALS is a neurodegenerative disorder affecting upper and lower motor neurons and resulting in fatal paralysis. Sensory abnormalities are absent. Death usually occurs within 2 to 5 years. The etiology of ALS is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Function
[TADBP_HUMAN] DNA and RNA-binding protein which regulates transcription and splicing. Involved in the regulation of CFTR splicing. It promotes CFTR exon 9 skipping by binding to the UG repeated motifs in the polymorphic region near the 3'-splice site of this exon. The resulting aberrant splicing is associated with pathological features typical of cystic fibrosis. May also be involved in microRNA biogenesis, apoptosis and cell division. Can repress HIV-1 transcription by binding to the HIV-1 long terminal repeat. Stabilizes the low molecular weight neurofilament (NFL) mRNA through a direct interaction with the 3' UTR.[14] [15]
Publication Abstract from PubMed
TDP-43 is a DNA/RNA binding protein associated with TDP-43 proteinopathies. Many mutations have been identified in the flexible C-terminal region, which is implicated in the disease pathology. We investigated four point mutations in the amyloidogenic core region (residues 311-360) of TDP-43 by biochemical and spectroscopic methods. We found that the G335D mutation enhances the aggregation and inclusion formation of TDP-43 and this mutant in TDP-35 (the C-terminal fragment of 35 kDa) exaggerates the antagonist effect on RNA processing by endogenous TDP-43; whereas Q343R gives an opposite effect. As a comparison, M337V and Q331K have very little impact on the aggregation and inclusion formation of TDP-43 or TDP-35. NMR structural analysis showed that the G335D mutant in the core region forms a loop linker between the two alpha-helices and promotes alpha-to-beta transition, but Q343R loses the second helix and consequently the structural transformation. Thus, the propensity of structural transformation in the amyloidogenic core of TDP-43 determines its aggregation and inclusion formation. This study may provide a molecular mechanism of the TDP-43 proteinopathies caused by genetic mutations.
Two mutations G335D and Q343R within the amyloidogenic core region of TDP-43 influence its aggregation and inclusion formation.,Jiang LL, Zhao J, Yin XF, He WT, Yang H, Che MX, Hu HY Sci Rep. 2016 Mar 31;6:23928. doi: 10.1038/srep23928. PMID:27030292[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Yokoseki A, Shiga A, Tan CF, Tagawa A, Kaneko H, Koyama A, Eguchi H, Tsujino A, Ikeuchi T, Kakita A, Okamoto K, Nishizawa M, Takahashi H, Onodera O. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 2008 Apr;63(4):538-42. doi: 10.1002/ana.21392. PMID:18438952 doi:10.1002/ana.21392
- ↑ Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, Clay D, Wood EM, Chen-Plotkin AS, Martinez-Lage M, Steinbart E, McCluskey L, Grossman M, Neumann M, Wu IL, Yang WS, Kalb R, Galasko DR, Montine TJ, Trojanowski JQ, Lee VM, Schellenberg GD, Yu CE. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008 May;7(5):409-16. doi: 10.1016/S1474-4422(08)70071-1. Epub, 2008 Apr 7. PMID:18396105 doi:10.1016/S1474-4422(08)70071-1
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- ↑ 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. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008 Mar 21;319(5870):1668-72. doi: 10.1126/science.1154584. Epub 2008, Feb 28. PMID:18309045 doi:10.1126/science.1154584
- ↑ Benajiba L, Le Ber I, Camuzat A, Lacoste M, Thomas-Anterion C, Couratier P, Legallic S, Salachas F, Hannequin D, Decousus M, Lacomblez L, Guedj E, Golfier V, Camu W, Dubois B, Campion D, Meininger V, Brice A. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol. 2009 Apr;65(4):470-3. doi: 10.1002/ana.21612. PMID:19350673 doi:10.1002/ana.21612
- ↑ Corrado L, Ratti A, Gellera C, Buratti E, Castellotti B, Carlomagno Y, Ticozzi N, Mazzini L, Testa L, Taroni F, Baralle FE, Silani V, D'Alfonso S. High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis. Hum Mutat. 2009 Apr;30(4):688-94. doi: 10.1002/humu.20950. PMID:19224587 doi:10.1002/humu.20950
- ↑ Borroni B, Bonvicini C, Alberici A, Buratti E, Agosti C, Archetti S, Papetti A, Stuani C, Di Luca M, Gennarelli M, Padovani A. Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. Hum Mutat. 2009 Nov;30(11):E974-83. doi: 10.1002/humu.21100. PMID:19655382 doi:10.1002/humu.21100
- ↑ Luquin N, Yu B, Saunderson RB, Trent RJ, Pamphlett R. Genetic variants in the promoter of TARDBP in sporadic amyotrophic lateral sclerosis. Neuromuscul Disord. 2009 Oct;19(10):696-700. doi: 10.1016/j.nmd.2009.07.005. Epub, 2009 Aug 19. PMID:19695877 doi:10.1016/j.nmd.2009.07.005
- ↑ Chio A, Borghero G, Pugliatti M, Ticca A, Calvo A, Moglia C, Mutani R, Brunetti M, Ossola I, Marrosu MG, Murru MR, Floris G, Cannas A, Parish LD, Cossu P, Abramzon Y, Johnson JO, Nalls MA, Arepalli S, Chong S, Hernandez DG, Traynor BJ, Restagno G. Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene. Arch Neurol. 2011 May;68(5):594-8. doi: 10.1001/archneurol.2010.352. Epub 2011, Jan 10. PMID:21220647 doi:10.1001/archneurol.2010.352
- ↑ Orru S, Manolakos E, Orru N, Kokotas H, Mascia V, Carcassi C, Petersen MB. High frequency of the TARDBP p.Ala382Thr mutation in Sardinian patients with amyotrophic lateral sclerosis. Clin Genet. 2012 Feb;81(2):172-8. doi: 10.1111/j.1399-0004.2011.01668.x. Epub, 2011 Apr 18. PMID:21418058 doi:10.1111/j.1399-0004.2011.01668.x
- ↑ Chiang HH, Andersen PM, Tysnes OB, Gredal O, Christensen PB, Graff C. Novel TARDBP mutations in Nordic ALS patients. J Hum Genet. 2012 May;57(5):316-9. doi: 10.1038/jhg.2012.24. Epub 2012 Mar 29. PMID:22456481 doi:10.1038/jhg.2012.24
- ↑ Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C, Shoesmith C. TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci. 2007 Jun;35(2):320-7. Epub 2007 Mar 20. PMID:17481916 doi:10.1016/j.mcn.2007.03.007
- ↑ Buratti E, Dork T, Zuccato E, Pagani F, Romano M, Baralle FE. Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J. 2001 Apr 2;20(7):1774-84. PMID:11285240 doi:10.1093/emboj/20.7.1774
- ↑ Jiang LL, Zhao J, Yin XF, He WT, Yang H, Che MX, Hu HY. Two mutations G335D and Q343R within the amyloidogenic core region of TDP-43 influence its aggregation and inclusion formation. Sci Rep. 2016 Mar 31;6:23928. doi: 10.1038/srep23928. PMID:27030292 doi:http://dx.doi.org/10.1038/srep23928
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