Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization.
Open accessAbstract
We have expressed six previously cloned isoforms of human microtubule-associated tau protein in Escherichia coli and purified them to homogeneity in a biologically active form. They range from 352 to 441 amino acids in length and differ from each other by the presence of three or four tandem repeats in the carboxy-terminal half and by the presence or absence of 29 or 58 amino acid inserts in the amino-terminus. When mixed together they gave a set of six bands on SDS-PAGE gels with apparent molecular weights of 48-67 kd and with a characteristic pattern of spacings. Four of these bands aligned with the major tau bands found in adult human cerebral cortex following perchloric acid extraction and alkaline phosphatase treatment. They consisted of isoforms with three repeats and no insertions, four repeats and no amino-terminal insertions and three- and four-repeat containing isoforms with the 29 amino acid insertion. In fetal human brain extracts treated with alkaline phosphatase one of the two major tau bands aligned with the three-repeat containing isoform with no insertions, whereas the molecular nature of the second major tau band remains to be established. The recombinant tau isoforms were biologically active at micromolar concentrations, as assessed by their ability to promote microtubule assembly. The rates of assembly were 2.5-3.0 times faster for isoforms containing four repeats when compared with three-repeat containing isoforms, with no significant contribution by the amino-terminal insertions.
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4R tau isoforms show a higher propensity to promote microtubule assembly compared to 3R tau isoforms.
“Since tau binds to microtubules through C-terminal repeats within the microtubule-binding domain, 4R tau isoforms show a higher propensity to promote microtubule assembly compared to 3R tau isoforms [122, 123].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [123]
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Tau Protein Modifications and Interactions: Their Role in Function and Dysfunction
Mietelska‐Porowska, A., Wasik, U., Goras, M., Filipek, A., & Niewiadomska, G. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15034671 · Cited by 407 · see citing works
“31, are expressed in the adult human brain [7].”
BackgroundGoode, B., & Feinstein, S. (1994) · The Journal of cell biology · doi:10.1083/jcb.124.5.769 · Cited by 399 · see citing works
Microtubule-associated protein tau in development, degeneration and protection of neurons
Wang, J., & Liu, F. (2008) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2008.03.002 · Cited by 395 · see citing works
Jensen, P. H., Hager, H., Nielsen, M. S., Højrup, P., Gliemann, J., & Jakes, R. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.36.25481 · Cited by 377 · see citing works
Self-citationGoedert, M., Jakes, R., Crowther, R. A., Cohen, P., Vanmechelen, E., Vandermeeren, M., & Cras, P. (1994) · Biochemical Journal · doi:10.1042/bj3010871 · Cited by 375 · see citing works
Self-citationThe complexity of tau in Alzheimer’s disease
Naseri, N. N., Wang, H., Guo, J. D., Sharma, M., & Luo, W. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.04.022 · Cited by 374 · see citing works
“4R tau demonstrates a stronger activity in promoting microtubule assembly than 3R tau does [39,40].”
BackgroundAxonopathy and amyotrophy in mice transgenic for human four-repeat tau protein
Probst, A., Götz, J., Wiederhold, K., Tolnay, M., Mistl, C., Jaton, A., Hong, M., Ishihara, T., Lee, V., Trojanowski, J., et al. (2000) · Acta Neuropathologica · doi:10.1007/s004010051148 · Cited by 362 · see citing works
Self-citationMutations causing neurodegenerative tauopathies
Goedert, M., & Jakes, R. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2004.08.007 · Cited by 438 · see citing works
“In normal adult human cerebral cortex, there are similar levels of three-repeat and four-repeat isoforms [10].”
BackgroundSelf-citationThe role of tau (MAPT) in frontotemporal dementia and related tauopathies
Rademakers, R., Cruts, M., & Broeckhoven, C. V. (2004) · Human Mutation · doi:10.1002/humu.20086 · Cited by 356 · see citing works
“, 2000] and assembles MTs more effectively as compared to 3R tau [Lee et al., 1989; Goedert and Jakes, 1990].”
BackgroundYamada, K., Cirrito, J. R., Stewart, F. R., Jiang, H., Finn, M. B., Holmes, B. B., Binder, L. I., Mandelkow, E.-M., Diamond, M. I., Lee, V. M.-Y., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.2569-11.2011 · Cited by 351 · see citing works
“The MTBR of recombinant tau was prepared as described previously (Goedert and Jakes, 1990) via exploiting the heat stability of tau protein followed by cation exchange chromatography.”
MethodNovak, M., Kabat, J., & Wischik, C. M. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05665.x · Cited by 398 · see citing works
Analysis of microtubule-associated protein tau glycation in paired helical filaments.
Ledesma, M. D., Bonay, P., Colaço, C., & Avila, J. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31849-5 · Cited by 333 · see citing works
Goedert, M., Jakes, R., Crowther, R. A., Six, J., Lübke, U., Vandermeeren, M., Cras, P., Trojanowski, J. Q., & Lee, V. M. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.11.5066 · Cited by 446 · see citing works
Self-citationTau exon 10 alternative splicing and tauopathies
Liu, F., & Gong, C.-X. (2008) · Molecular Neurodegeneration · doi:10.1186/1750-1326-3-8 · Cited by 323 · see citing works
“On the other hand, tau isoforms with 2 inserts (2N), 1 insert (1N) and 0 insert (0N) in the N-terminal region comprise ~54%, ~37% and ~9%, respectively, of total tau [8,20].”
Proteasomal degradation of tau protein
David, D. C., Layfield, R., Serpell, L., Narain, Y., Goedert, M., & Spillantini, M. G. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01137.x · Cited by 327 · see citing works
“Recombinant tau43 and tau46 proteins were expressed and purified as described (Goedert and Jakes 1990).”
MethodSelf-citationTau pathophysiology in neurodegeneration: a tangled issue
Spires‐Jones, T. L., Stoothoff, W. H., de Calignon, A., Jones, P., & Hyman, B. T. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2008.11.007 · Cited by 317 · see citing works
Naini, S. M. A., & Soussi‐Yanicostas, N. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/151979 · Cited by 318 · see citing works
“The 3R- and 4R-tau isoforms are found in equal amounts in the adult human brain; while the 0N, 1N, and 2N tau isoforms comprise about 37%, 54%, and 9% of total tau, respectively [15, 16] (Figure 1).”
BackgroundSpittaels, K., den Haute, C. V., Dorpe, J. V., Geerts, H., Mercken, M. H., Bruynseels, K., Lasrado, R., Vandezande, K., Laenen, I., Boon, T., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m006219200 · Cited by 317 · see citing works
Molecular characterization of microtubule-associated proteins tau and map2
Goedert, M., Crowther, R. A., & Garner, C. C. (1991) · Trends in Neurosciences · doi:10.1016/0166-2236(91)90105-4 · Cited by 315 · see citing works
Self-citationYamamoto, A., Shin, R., Hasegawa, K., Naiki, H., Sato, H., Yoshimasu, F., & Kitamoto, T. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.t01-1-01061.x · Cited by 313 · see citing works
“Assessment of in vitro interaction of iron (III) and aluminum (III) with wild versus cysteine-free s expressed in COS7 cells The recombinant s cDNA htau40 encoding the longest 441-amino acid isoform (Goedert et al. 1989; Goedert and Jakes 1990) was”
MethodTau protein as a differential biomarker of tauopathies
Sergeant, N., Delacourte, A., & Buée, L. (2004) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2004.06.020 · Cited by 312 · see citing works
“It has been demonstrated that adult Tau isoforms with 4R (R1–R4) are more efficient at promoting microtubule assembly than the fetal isoform with 3R (R1, R3, R4) [18,44,45].”
BackgroundDuff, K., Knight, H., Refolo, L. M., Sanders, S., Yu, X., Picciano, M., Malester, B., Hutton, M. L., Adamson, J., Goedert, M., et al. (2000) · Neurobiology of Disease · doi:10.1006/nbdi.1999.0279 · Cited by 311 · see citing works
Self-citationPhosphorylation of microtubule‐associated protein tau by stress‐activated protein kinases
Goedert, M., Hasegawa, M., Jakes, R., Lawler, S., Cuenda, A., & Cohen, P. R. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00483-3 · Cited by 308 · see citing works
Self-citationMechanisms of secretion and spreading of pathological tau protein
Brunello, C. A., Merezhko, M., Uronen, R.-L., & Huttunen, H. J. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03349-1 · Cited by 304 · see citing works
Detection of Phosphorylated Ser262 in Fetal Tau, Adult Tau, and Paired Helical Filament Tau
Seubert, P., Mawal-Dewan, M., Barbour, R., Jakes, R., Goedert, M., Johnson, G. V. W., Litersky, J. M., Schenk, D., Lieberburg, I., Trojanowski, J. Q., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.32.18917 · Cited by 345 · see citing works
Self-citationGoode, B. L., Denis, P. E., Panda, D., Radeke, M. J., Miller, H. P., Wilson, L., & Feinstein, S. C. (1997) · Molecular Biology of the Cell · doi:10.1091/mbc.8.2.353 · Cited by 296 · see citing works
Tau Pathology in Two Dutch Families with Mutations in the Microtubule-Binding Region of Tau
Spillantini, M. G., Crowther, R. A., Kamphorst, W., Heutink, P., & Swieten, J. C. V. (1998) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65721-5 · Cited by 293 · see citing works
A walk through tau therapeutic strategies
Jadhav, S., Ávila, J., Schöll, M., Kovács, G. G., Kövari, E., Škrabana, R., Evans, L., Kontseková, E., Malawska, B., de Silva, R., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0664-z · Cited by 286 · see citing works
Overexpression of tau in a nonneuronal cell induces long cellular processes.
Knops, J., Kosik, K. S., Lee, G., Pardee, J. D., Cohen-Gould, L., & McConlogue, L. (1991) · The Journal of cell biology · doi:10.1083/jcb.114.4.725 · Cited by 286 · see citing works
Berriman, J. A., Serpell, L. C., Oberg, K. A., Fink, A. L., Goedert, M., & Crowther, R. A. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1530287100 · Cited by 288 · see citing works
Self-citationAccelerated filament formation from tau protein with specific FTDP‐17 missense mutations
Nacharaju, P., Lewis, J. M., Easson, C., Yen, S. H., Hackett, J., Hutton, M., & Yen, S.-H. C. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00294-x · Cited by 283 · see citing works
Microtubule-Associated Protein Tau
Yen, S.-H. C., Nacharaju, P., Ko, L., Kenessey, Á., & Liu, W.-K. (1998) · Elsevier eBooks · doi:10.1016/b978-012734610-6/50012-9 · Cited by 284 · see citing works
Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1
Sergeant, N. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.19.2143 · Cited by 281 · see citing works
“For analysis of the expression of tau proteins isoforms, a homogenate containing the six recombinant human tau isoforms (77) was provided by Michel Goedert (MRC, Cambridge, UK), as described previously (38,77).”
MethodPanda, D., Samuel, J. C., Massie, M., Feinstein, S. C., & Wilson, L. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1633508100 · Cited by 280 · see citing works
Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability
Alonso, A. D., Cohen, L. S., Corbo, C., Morozova, V., ElIdrissi, A., Phillips, G., & Kleiman, F. E. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00338 · Cited by 278 · see citing works
“When analyzed in microtubule polymerization reactions, recombinant proteins representing each of these six tau isoforms and the 3R proteins had slower rates of polymerization than 4R proteins independently of the N-terminal composition (Goedert and Jakes, 1990).”
BackgroundTemplate-assisted filament growth by parallel stacking of tau
Margittai, M., & Langen, R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401911101 · Cited by 276 · see citing works
Interface between tauopathies and synucleinopathies: A tale of two proteins
Galpern, W. R., & Lang, A. E. (2006) · Annals of Neurology · doi:10.1002/ana.20819 · Cited by 263 · see citing works
Effects of frontotemporal dementia FTDP‐17 mutations on heparin‐induced assembly of tau filaments
Goedert, M., Jakes, R., & Crowther, R. A. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00508-6 · Cited by 260 · see citing works
Self-citationHallmarks of Alzheimer’s Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain
Espuny-Camacho, I., Arranz, A. M., Fiers, M., Snellinx, A., Ando, K., Munck, S., Bonnefont, J., Lambot, L., Corthout, N., Omodho, L., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.02.001 · Cited by 244 · see citing works
“During human brain embryonic development, only the 3R splice form of Tau is detected, while the adult human brain expresses 3R and 4R Tau splice forms in a 1:1 ratio (Goedert and Jakes, 1990).”
BackgroundCloning of a big tau microtubule-associated protein characteristic of the peripheral nervous system.
Goedert, M., Spillantini, M. G., & Crowther, R. A. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.5.1983 · Cited by 255 · see citing works
Self-citationWagner, U., Utton, M. A., Gallo, J., & Miller, C. C. J. (1996) · Journal of Cell Science · doi:10.1242/jcs.109.6.1537 · Cited by 255 · see citing works
“Tau binds to microtubules and promotes microtubule assembly in vitro (Goedert and Jakes, 1990) and probably functions in the formation and maintenance of axons since down-regulation of tau expression in primary cerebellar neurones with antisense oligonucleotides inhibits the ability of these cells to generate axons (C…”
Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo
Bolós, M., Llorens-Martín, M., Jurado-Arjona, J., Hernández, F., Rábano, A., & Avila, J. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-150704 · Cited by 234 · see citing works
Varani, L., Hasegawa, M., Spillantini, M. G., Smith, M. J., Murrell, J. R., Ghetti, B. F., Klug, A., Goedert, M., & Varani, G. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.14.8229 · Cited by 248 · see citing works
Self-citationYamamoto, A., Shin, R., Hasegawa, K., Naiki, H., Sato, H., YOSHIMASU, F., & Kitamoto, T. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01061.x · Cited by 246 · see citing works
Structural Principles of Tau and the Paired Helical Filaments of Alzheimer's Disease
Mandelkow, E., Von Bergen, M., Biernat, J., & Mandelkow, E. (2007) · Brain Pathology · doi:10.1111/j.1750-3639.2007.00053.x · Cited by 243 · see citing works
“In adult human brain, there is a balance of 3R and 4R isoforms, all of which assemble into PHFs (44, 66).”
BackgroundExtracellular tau is toxic to neuronal cells
Gómez-Ramos, A., Díaz-Hernández, M., Cuadros, R., Hernández, F., & Avila, J. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.07.078 · Cited by 241 · see citing works
“Protein purification The recombinant tau protein isoform (tau 42) containing 2 N-terminal inserts and 4 microtubule binding repeats [20]; the same isoform of tau bearing the mutations G272V, P301L and R406W (tauvlw: [21]); the tau fragment 2R containing the first and third microtubule binding repeats; and the tau 42 i…”
BackgroundMethodStructural and Functional Differences between 3-Repeat and 4-Repeat Tau Isoforms
Goode, B. L., Chau, M. F., Denis, P. E., & Feinstein, S. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m007489200 · Cited by 241 · see citing works
Cellular and pathological functions of tau
Bravo, C. P., Naguib, S. A., & Gan, L. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00753-9 · Cited by 245 · see citing works
Gómez‐Ramos, A., Dı́az-Hernández, M., Rubio, A., Miras‐Portugal, M. T., & Ávila, J. (2008) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2007.12.010 · Cited by 233 · see citing works
Yoshida, H., & Ihara, Y. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb03642.x · Cited by 232 · see citing works
Tau Cleavage and Dephosphorylation in Cerebellar Granule Neurons Undergoing Apoptosis
Canu, N., Dus, L., Barbato, C., Ciotti, M. T., Brancolini, C., Rinaldi, A. M., Novak, M., Cattaneo, A., Bradbury, A., & Calissano, P. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-18-07061.1998 · Cited by 232 · see citing works
“binding repeats (Goedert and Jakes, 1990), (2) the proline-rich”
BackgroundAbsence of CX3CR1 impairs the internalization of Tau by microglia
Bolós, M., Llorens-Martín, M., Perea, J. R., Jurado-Arjona, J., Rábano, A., Hernández, F., & Avila, J. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0200-1 · Cited by 231 · see citing works
“The recombinant human Tau isoform containing 2 Nterminal inserts and 4 microtubule binding repeats (Tau42 [24]) was isolated as described previously [25].”
MethodBrandt, R., & Lee, G. S. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53710-8 · Cited by 229 · see citing works
Thomas, G. M., Frame, S., Goedert, M., Näthke, I. S., Polakis, P. G., & Cohen, P. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01161-8 · Cited by 229 · see citing works
Self-citationPaleologou, K. E., Kragh, C. L., Mann, D. M. A., Salem, S. A., Al‐Shami, R., Allsop, D., Hassan, A. H. M., Jensen, P. H., & El‐Agnaf, O. M. A. (2008) · Brain · doi:10.1093/brain/awn349 · Cited by 228 · see citing works
Expression of tau protein in non-neuronal cells: microtubule binding and stabilization
Lee, G. S., & Rook, S. L. (1992) · Journal of Cell Science · doi:10.1242/jcs.102.2.227 · Cited by 226 · see citing works
Goedert, M., Cohen, E. S., Jakes, R., & Cohen, P. (1992) · FEBS Letters · doi:10.1016/0014-5793(92)81418-l · Cited by 272 · see citing works
Self-citationConformational Diversity of Wild-type Tau Fibrils Specified by Templated Conformation Change
Frost, B., Ollesch, J., Wille, H., & Diamond, M. I. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m805627200 · Cited by 224 · see citing works
- Authors
- Goedert, M., & Jakes, R.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- ORCID
- Goedert, M.
- Venue
- The EMBO Journal
- Published
- 1990-12-01
- Volume
- 9
- Issue
- 13
- Pages
- 4225-4230
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC552204
- OpenAlex
- W1509571186
- Cited by
- 929
- References
- 46
- Citations by year
- 2026: 23 · 2025: 29 · 2024: 50 · 2023: 39 · 2022: 40 · 2021: 53 · 2020: 34 · 2019: 39 · 2018: 42 · 2017: 41 · 2016: 27 · 2015: 37 · 2014: 18 · 2013: 21 · 2012: 25
- FWCI
- 15.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, tau isoforms, microtubule-associated proteins, microtubule assembly, tandem repeats, recombinant protein expression, cerebral cortex, fetal brain
- MeSH terms
- Aged, Alkaline Phosphatase, Alzheimer Disease, Amino Acid Sequence, Brain, Escherichia coli, Humans, Isomerism, Microtubule-Associated Proteins, Middle Aged, Molecular Sequence Data, Recombinant Proteins, Repetitive Sequences, Nucleic Acid, RNA Splicing, RNA, Messenger, Tubulin, Mutagenesis, Site-Directed, tau Proteins
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