An amyloid-like pathological conformation of TDP-43 is stabilized by hypercooperative hydrogen bonds

Frontiers in Molecular Neuroscience

Volumn 9, Issue NOV2016, 2016, Pages

  Mompeán, Miguel ^a   Baralle, Marco ^b   Buratti, Emanuele ^b   Laurents, Douglas V ^a  

^a INSTITUTO DE QUÍMICA FÍSICA ROCASOLANO   (Spain)

^b INTERNATIONAL CENTRE FOR GENETIC ENGINEERING AND BIOTECHNOLOGY   (Italy)

Author keywords

Amyotrophic lateral sclerosis (ALS); Frontotemporal lobar degeneration; HnRNPs; Hyperstable H bonds; Pathological amyloids; Protein misfolding and disease; Transitive response DNA bonding protein 43 kDa (TDP 43)

Indexed keywords

AMYLOID; ASPARAGINE; GLUTAMINE; OLIGOMER; RNA; TAR DNA BINDING PROTEIN;

ARTICLE; BINDING AFFINITY; CARBOXY TERMINAL SEQUENCE; COMPUTER ANALYSIS; CONFORMATION; DEAMINATION; DIMERIZATION; GENE MUTATION; HYDROGEN BOND; IMMUNOHISTOCHEMISTRY; MOLECULAR DYNAMICS; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PROTEIN INTERACTION; PROTEIN PHOSPHORYLATION;

EID: 84995931542     PISSN: 16625099     EISSN: None     Source Type: Journal    
DOI: 10.3389/fnmol.2016.00125     Document Type: Article

References (56)

1. Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., et al. (2006). TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602-611. doi: 10.1016/j.bbrc.2006.10.093
2. Ayala, Y. M., Pantano, S., D’Ambrogio, A., Buratti, E., Brindisi, A., Marchetti, C., et al. (2005). Human, Drosophila and C. elegans TDP-43: nucleic acid binding properties and splicing regulatory function. J. Mol. Biol. 348, 575-588. doi: 10.1016/j.jmb.2005.02.038
3. Bigio, E. H., Wu, J. Y., Deng, H.-X., Bit-Ivan, E. N., Mao, Q., Ganti, R., et al. (2013). Inclusions in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), but not FTLD with FUS proteinopathy (FTLD-FUS) have properties of amyloid. Acta Neuropathol. 125, 463-465. doi: 10.1007/s00401-013-1089-6
4. Brady, O. A., Meng, P., Zheng, Y., Mao, Y., and Hu, F. (2011). Regulation of TDP-43 aggregation by phosphorylation and p62/SQSTM1. J. Neurochem. 116, 248-259. doi: 10.1111/j.1471-4159.2010.07098.x
5. Budini, M., Buratti, E., Stuani, C., Guarnaccia, C., Romano, V., De Conti, L., et al. (2012). Cellular model of TAR DNA-binding protein 43 (TDP-43) aggregation based on its C-terminal Gln/Asn-rich region. J. Biol. Chem. 287, 7512-7525. doi: 10.1074/jbc.m111.288720
6. Budini, M., Romano, V., Quadri, Z., Buratti, E., and Baralle, F. E. (2015). TDP-43 loss of cellular function through aggregation requires additional structural determinants beyond its C-terminal Q/N prion-like domain. Hum. Mol. Genet. 24, 9-20. doi: 10.1093/hmg/ddu415
7. Buratti, E. (2016). Functional significance of TDP-43 mutations in disease. Adv. Genet. 91, 1-53. doi: 10.1016/bs.adgen.2015.07.001
8. Buratti, E., and Baralle, F. E. (2011). TDP-43: new aspects of autoregulation mechanisms in RNA binding proteins and their connection with human disease. FEBS J. 278, 3530-3538. doi: 10.1111/j.1742-4658.2011.08257.x
9. Buratti, E., and Baralle, F. E. (2012). TDP-43: gumming up neurons through protein-protein and protein-RNA interactions. Trends Biochem. Sci. 37, 237-247. doi: 10.1016/j.tibs.2012.03.003
10. Cairns, N. J., Neumann, M., Bigio, E. H., Holm, I. E., Troost, D., Hatanpaa, K. J., et al. (2007). TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am. J. Pathol. 171, 227-240. doi: 10.2353/ajpath.2007.070182
11. Capitini, C., Conti, S., Perni, M., Guidi, F., Cascella, R., De Poli, A., et al. (2014). TDP-43 inclusion bodies formed in bacteria are structurally amorphous, non-amyloid and inherently toxic to neuroblastoma cells. PLoS One 9:e86720. doi: 10.1371/journal.pone.0086720
12. Chen, A. K.-H., Lin, R. Y.-Y., Hsieh, E. Z.-J., Tu, P.-H., Chen, R. P.-Y., Liao, T.-Y., et al. (2010). Induction of amyloid fibrils by the C-terminal fragments of TDP-43 in amyotrophic lateral sclerosis. J. Am. Chem. Soc. 132, 1186-1187. doi: 10.1021/ja9066207
13. Espargaró, A., Busquets, M. A., Estelrich, J., and Sabate, R. (2016). Key points concerning amyloid infectivity and prion-like neuronal invasion. Front. Mol. Neurosci. 9:29. doi: 10.3389/fnmol.2016.00029
14. Fang, Y.-S., Tsai, K.-J., Chang, Y.-J., Kao, P., Woods, R., Kuo, P.-H., et al. (2014). Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients. Nat. Commun. 5:4824. doi: 10.1038/ncomms5824
15. Fuentealba, R. A., Udan, M., Bell, S., Wegorzewska, I., Shao, J., Diamond, M. I., et al. (2010). Interaction with polyglutamine aggregates reveals a Q/N-rich domain in TDP-43. J. Biol. Chem. 285, 26304-26314. doi: 10.1074/jbc.M110.125039
16. Guo, W., Chen, Y., Zhou, X., Kar, A., Ray, P., Chen, X., et al. (2011). An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nat. Struct. Mol. Biol. 18, 822-830. doi: 10.1038/nsmb.2053
17. Hasegawa, M., Arai, T., Nonaka, T., Kametani, F., Yoshida, M., Hashizume, Y., et al. (2008). Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann. Neurol. 64, 60-70. doi: 10.1002/ana.21425
18. Jiang, L.-L., Che, M.-X., Zhao, J., Zhou, C.-J., Xie, M.-Y., Li, H.-Y., et al. (2013). Structural transformation of the amyloidogenic core region of TDP-43 protein initiates its aggregation and cytoplasmic inclusion. J. Biol. Chem. 288, 19614-19624. doi: 10.1074/jbc.M113.463828
19. Johnson, B. S., McCaffery, S. M., Lindquist, S., and Gilter, A. D. (2008). A yeast TDP-43 protein pathology model: exploring the molecular determinants of TDP-43 aggregation and cellular toxicity. Proc. Natl. Acad. Sci. U S A 105, 6439-6444. doi: 10.1073/pnas.0802082105
20. Kametani, F., Nonaka, T., Suzuki, T., Arai, T., Dohmae, N., Akiyama, H., et al. (2009). Identification of casein kinase-1 phosphorylation sites on TDP-43. Biochem. Biophys. Res. Commun. 382, 405-409. doi: 10.1016/j.bbrc.2009.03.038
21. Kametani, F., Obi, T., Shishido, T., Akatsu, H., Murayama, S., Saito, Y., et al. (2016). Mass spectrometric analysis of accumulated TDP-43 in amyotrophic later sclerosis brains. Sci. Rep. 6:23281. doi: 10.1038/srep23281
22. Kato, M., Han, T. W., Xie, S., Shi, K., Du, X., Wu, L. C., et al. (2012). Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149, 753-767. doi: 10.1016/j.cell.2012.04.017
23. Kiernan, M. C., Vucic, S., Cheah, B. C., Turner, M. R., Eisen, A., Hardiman, O., et al. (2011). Amyotrophoic lateral sclerosis. Lancet 377, 942-955. doi: 10.1016/S0140-6736(10)61156-7
24. Kuo, P.-H., Doudeva, L. G., Wang, Y.-T., Shen, C.-K. J., and Yuan, H. S. (2009). Structural insights into TDP-43 in nucleic-acid binding and domain interactions. Nucleic Acids Res. 37, 1799-1808. doi: 10.1093/nar/gkp013
25. Leigh, P. N., Whitwell, H., Garofalo, O., Buller, J., Swash, M., Martin, J. E., et al. (1991). Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophoic lateral sclerosis. Morphology, distribution and specificity. Brain 114, 775-788. doi: 10.1093/brain/114.2.775
26. Li, H.-Y., Yeh, P.-A., Chiu, H.-C., Tang, C.-Y., and Tu, B. P. (2011). Hyperphosphorylation as a defense mechanism to reduce TDP-43 aggregation. PLoS One 6:e23075. doi: 10.1371/journal.pone.0023075
27. Lim, L., Wei, Y., Lu, Y., and Song, J. (2016). ALS-causing mutations significantly perturb the self-assembly and interactions with nucleic acid of the intrinsically disordered prion-like domain of TDP-43. PLoS Biol. 14:e1002338. doi: 10.1371/journal.pbio.1002338
28. Lin, W. L., and Dickson, D. W. (2008). Ultrastructural localization of TDP-43 in filamentous neuronal inclusions in various neurodegenerative diseases. Acta Neuropathol. 116, 205-213. doi: 10.1007/s00401-008-0408-9
29. Lukavsky, P. J., Daujotyte, D., Tollervey, J. R., Ule, J., Stuani, C., Buratti, E., et al. (2013). Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43. Nat. Struct. Mol. Biol. 20, 1443-1449. doi: 10.1038/nsmb.2698
30. Mackenzie, I. R. A., Neumann, M., Baborie, A., Sampathu, D. M., Du Plessis, D., Jaros, E., et al. (2011). A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol. 122, 111-113. doi: 10.1007/s00401-011-0845-8
31. Mackness, B. C., Tran, M. T., McClain, S. P., Matthews, C. R., and Zitzewitz, J. A. (2014). Folding of the RNA recognition motif (RRM) domains of the amyotrophic lateral sclerosis (ALS)-linked protein TDP-43 reveal an intermediate state. J. Biol. Chem. 289, 8264-8276. doi: 10.1074/jbc.M113.542779
32. Mompeán, M., Buratti, E., Guarnaccia, C., Brito, R. M. M., Chakrabartty, A., Baralle, F. E., et al. (2014). Structural characterization of the minimal segment of TDP-43 competent for aggregation. Arch. Biochem. Biophys. 545, 53-62. doi: 10.1016/j.abb.2014.01.007
33. Mompeán, M., Chakrabartty, A., Buratti, E., and Laurents, D. V. (2016a). Electrostatic repulsion governs TDP-43 C-terminal domain aggregation. PLoS Biol. 14:e1002447. doi: 10.1371/journal.pbio.1002447
34. Mompeán, M., Nogales, A., Ezquerra, T. A., and Laurents, D. V. (2016b). Complex system assembly underlies a two-tiered model of highly delocalized electrons. J. Phys. Chem. Lett. 7, 1859-1864. doi: 10.1021/acs.jpclett.6b00699
35. Mompeán, M., Romano, V., Pantoja-Uceda, D., Stuani, C., Baralle, F. E., Buratti, E., et al. (2016c). The TDP-43 N-terminal domain structure at high resolution. FEBS J. 283, 1242-1260. doi: 10.1111/febs.13651
36. Mompeán, M., Hervás, R., Xu, Y., Tran, T. H., Guarnaccia, C., Buratti, E., et al. (2015). Structural evidence of amyloid fibril formation in the putative aggregation domain of TDP-43. J. Phys. Chem. Lett. 6, 2608-2615. doi: 10.1021/acs.jpclett.5b00918
37. Neumann, M., Kwong, L. K., Lee, E. B., Kremmer, E., Flatley, A., Xu, Y., et al. (2009). Phosphorylation of S409/S410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinpathies. Acta Neuropathol. 117, 137-149. doi: 10.1007/s00401-008-0477-9
38. Neumann, M., Kwong, L. K., Sampathu, D. M., Trojanowski, J. Q., and Lee, V. M.-Y. (2007). TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophoic lateral sclerosis: protein misfolding diseases without amyloidosis. Arch. Neurol. 64, 1388-1394. doi: 10.1001/archneur.64.10.1388
39. Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., et al. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130-133. doi: 10.1126/science.1134108
40. Nonaka, T., Masuda-Suzukake, M., Arai, T., Hasegawa, Y., Akatsu, H., Obi, T., et al. (2013). Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep. 4, 124-134. doi: 10.1016/j.celrep.2013.06.007
41. Patel, A., Lee, H. O., Jawerth, L., Maharama, S., Jahnel, M., Hein, M. Y., et al. (2015). A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162, 1066-1077. doi: 10.1016/j.cell.2015.07.047
42. Pesiridis, G. S., Lee, V. M.-Y., and Trojanowski, J. Q. (2009). Mutations in TDP-43 link glycine-rich domain function to amyotrophic lateral sclerosis. Hum. Mol. Genet. 18, R156-R162. doi: 10.1093/hmg/ddp303
43. Polymenidou, M., Lagier-Tourenne, C., Hutt, K. R., Huelga, S. C., Moran, J., Liang, T. Y., et al. (2011). Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat. Neurosci. 14, 459-468. doi: 10.1038/nn.2779
44. Qin, H., Lim, L.-Z., Wei, Y., and Song, J. (2014). TDP-43 N-terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium that can be shifted by binding to ssDNA. Proc. Natl. Acad. Sci. U S A 111, 18619-18624. doi: 10.1073/pnas.1413994112
45. Robinson, J. L., Geser, F., Stieber, A., Umoh, M., Kwong, L. K., Van Deerlin, V. M., et al. (2013). TDP-43 skeins show properties of amyloid in a subset of ALS cases. Acta Neuropathol. 125, 121-131. doi: 10.1007/s00401-012-1055-8
46. Romano, V., Quadri, Z., Baralle, F. E., and Buratti, E. (2015). The structural integrity of TDP-43 N-terminus is required for efficient aggregate entrapment and consequent loss of protein function. Prion 9, 1-9. doi: 10.1080/19336896.2015.1011885
47. Saini, A., and Chauhan, V. S. (2011). Delineation of the core aggregation sequences of TDP-43 C-terminal fragment. Chembiochem 12, 2495-2501. doi: 10.1002/cbic.201100427
48. Saini, A., and Chauhan, V. S. (2014). Self-assembling properties of peptides derived from TDP-43 C-terminal fragment. Langmuir 30, 3845-3856. doi: 10.1021/la404710w
49. Sasaguri, H., Chew, J., Xu, Y. F., Gendron, T. F., Garrett, A., Lee, C. W., et al. (2016). The extreme N-terminus of TDP-43 mediates the cytoplasmic aggregation of TDP-43 and associated toxicity in vivo. Brain Res. 1647, 57-64. doi: 10.1016/j.brainres.2016.04.069
50. Smethurst, P., Sidle, K. C., and Hardy, J. (2015). Review: prion-like mechanisms of transactive response DNA binding protein of 43 kDa (TDP-43) in amyotrophic lateral sclerosis (ALS). Neuropathol. Appl. Neurobiol. 41, 578-597. doi: 10.1111/nan.12206
51. Sun, C.-S., Wang, C. Y.-H., Chen, B. P.-W., He, R.-Y., Liu, G. C.-H., Wang, C.-H., et al. (2014). The influence of pathological mutations and proline substitutions in TDP-43 glycine rich peptides on its amyloid properties and celular toxicity. PLoS One 9:e103644. doi: 10.1371/journal.pone.0103644
52. Thorpe, J. R., Tang, H., Atherton, J., and Cairns, N. J. (2008). Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinpathy. J. Neural Transm. (Vienna) 115, 1661-1671. doi: 10.1007/s00702-008-0137-1
53. Tollervey, J. R., Curk, T., Rogelj, B., Briese, M., Cereda, M., Kayikci, M., et al. (2011). Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci. 14, 452-458. doi: 10.1038/nn.2778
54. Wang, Y.-T., Kuo, P.-H., Chiang, C.-H., Liang, J.-R., Chen, Y.-R., Wang, S., et al. (2013). The truncated C-terminal RNA recognition motif of TDP-43 protein plays a key role in forming proteinaceous aggregates. J. Biol. Chem. 288, 9049-9057. doi: 10.1074/jbc.M112.438564
55. Zhang, Y.-J., Caulfield, T., Xu, Y.-F., Gendron, T. F., Hubbard, J., Stetler, C., et al. (2013). The dual functions of the extreme N-terminus of TDP-43 in regulating its biological activity and inclusion formation. Hum. Mol. Genet. 22, 3112-3122. doi: 10.1093/hmg/ddt166
56. Zhu, L., Xu, M., Yang, M., Yang, Y., Li, Y., Deng, J., et al. (2014). An ALS-mutant TDP-43 neurotoxic peptide adopts an anti-parallel β-structure and induces TDP-43 redistribution. Hum. Mol. Genet. 23, 6863-6877. doi: 10.1093/hmg/ddu409