Cited by 929Alzheimer's disease research and treatmentsMicrotubule and mitosis dynamicsNeuroinflammation and Neurodegeneration Mechanisms

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Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization.

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Goedert, M., Jakes, R.·1990·The EMBO Journal

DOI 10.1002/j.1460-2075.1990.tb07870.xPMC PMC552204

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Abstract

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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“As exon 10 encodes an additional microtubule binding domain its inclusion enhances the microtubule-binding activity of s (Goedert and Jakes, 1990; Lu and Kosik, 2001).”
Background
Specific macromolecular interactions between tau and the microtubule system
Far�as, G. A., Vial, C., & Maccioni, R. B. (1992) · Molecular and Cellular Biochemistry · doi:10.1007/bf00229646 · Cited by 20
“1) are equivalent to the first (V247-G264), third (V3°9-G 326) and fourth (V341-G 358) tau repeats found in some isoforms of the adult brain [11, 30].”
Background
Differential diagnosis of neurodegenerative diseases with special emphasis on Creutzfeldt-Jakob disease
Otto, M., & Wiltfang, J. (2003) · Restorative Neurology and Neuroscience · doi:10.3233/rnn-2003-00238 · Cited by 20
“In the brain of an adult, the ratio of 3R-tau to 4R-tau isoforms is around 1:1 [159].”
Evolving concepts of chronic traumatic encephalopathy as a neuropathological entity
Ling, H., Neal, J., & Révész, T. (2017) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12425 · Cited by 19
Focal cerebral ischemia induces changes in oligodendrocytic tau isoforms in the damaged area
Villa-González, M., Vallés‐Saiz, L., Hernández, I. H., Ávila, J., Hernández, F., & Pérez-Álvarez, M. J. (2020) · Glia · doi:10.1002/glia.23865 · Cited by 19
“The six adult isoforms vary in the presence or absence of Exons 2, 3, and 10 (Goedert & Jakes, 1990).”
Background
Mical modulates Tau toxicity via cysteine oxidation in vivo
Prifti, E., Tsakiri, E. N., Vourkou, E., Stamatakis, G. M., Samiotaki, M. K., Skoulakis, E. M. C., & Papanikolopoulou, K. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01348-1 · Cited by 21
“a greater affinity than 3R species and extensive phosphorylation reduces binding efficiency [4, 5].”
Background
Populations of Tau Conformers Drive Prion-like Strain Effects in Alzheimer’s Disease and Related Dementias
Hromádková, L., Siddiqi, M. K., Liu, H., & Safar, J. (2022) · Cells · doi:10.3390/cells11192997 · Cited by 19
“Overall, alternative splicing results in six tau isoforms that differ by the presence or absence of two N-terminal regions (0 N, 1 N, or 2 N) as well as conserved repeat motifs (3R or 4R) [94,95].”
Background
Differential Binding and Conformational Dynamics of Tau Microtubule-Binding Repeats with a Preformed Amyloid-β Fibril Seed
Song, Z., Gatch, A. J., Sun, Y., & Ding, F. (2023) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00014 · Cited by 21
Hypothermic Preconditioning Reverses Tau Ontogenesis in Human Cortical Neurons and is Mimicked by Protein Phosphatase 2A Inhibition
Rzechorzek, N. M., Connick, P., Livesey, M. R., Borooah, S., Patani, R., Burr, K., Story, D., Wyllie, D. J. A., Hardingham, G. E., & Chandran, S. (2015) · EBioMedicine · doi:10.1016/j.ebiom.2015.12.010 · Cited by 20
“These isoforms differ by their number of repeated microtubule binding domains; three repeat (3R) tau predominates during early development, whilst approximately equal levels of 3R and 4R tau exist in the mature brain (Goedert et al., 1989b; Goedert and Jakes, 1990).”
Background
Increased 4R tau expression and behavioural changes in a novel MAPT-N296H genomic mouse model of tauopathy
Wobst, H. J., Denk, F., Oliver, P., Livieratos, A., Taylor, T. N., Knudsen, M. H., Bengoa-Vergniory, N., Bannerman, D., & Wade-Martins, R. (2017) · Scientific Reports · doi:10.1038/srep43198 · Cited by 17
From 1997 to 2007: A decade journey through the H1 haplotype on 17q21 chromosome
Kalinderi, K., Fidani, L., & Bostantjopoulou, S. (2008) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2008.03.001 · Cited by 19
“The 4R tau isoform binds to microtubules threefold more strongly and assembles microtubules more efficiently than 3R tau [6].”
Background
The pathology of the neuronal cytoskeleton in Alzheimer's disease
Brion, J. (1992) · Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology · doi:10.1016/0167-4838(92)90047-h · Cited by 19
Tau protein aggregation associated with SARS-CoV-2 main protease
Eberle, R. J., Coronado, M. A., Gering, I., Sommerhage, S., Korostov, K., Stefanski, A., Stühler, K., Kraemer‐Schulien, V., Blömeke, L., Bannach, O., et al. (2023) · PLoS ONE · doi:10.1371/journal.pone.0288138 · Cited by 19
“However, the protein presented a single band on a denaturing SDS-PAGE gel with an apparent molecular mass of around 67 kDa, this behavior was described previously [42, 43].”
Background
ADNP: in search for molecular mechanisms and innovative therapeutic strategies for frontotemporal degeneration
Gozes, I., & Ivashko‐Pachima, Y. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00205 · Cited by 18
“…splicing around exon 10 of the tau transcript yields tau protein variants including tau protein containing either 3 or 4 microtubule binding repeat domains (tau 3R or 4R), associated with dynamic and stable microtubules, respectively (Goedert et al., 1988, 1989a,b; Goedert and Jakes, 1990).”
Background
Elevation of casein kinase 1ε associated with TDP‐43 and tau pathologies in Alzheimer's disease
Gu, J., Hu, W. H., Tan, X., Qu, S., Chu, D., Gong, C., Iqbal, K., & Liu, F. (2019) · Brain Pathology · doi:10.1111/bpa.12775 · Cited by 19
“In normal adult human brain, approximately equal levels of 3R- and 4R-tau are expressed (18).”
Background
Differential compartmental processing and phosphorylation of pathogenic human tau and native mouse tau in the line 66 model of frontotemporal dementia
Lemke, N., Melis, V., Lauer, D., Magbagbeolu, M., Neumann, B., Harrington, C. R., Riedel, G., Wischik, C. M., Theuring, F., & Schwab, K. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014890 · Cited by 15
“This has been shown to be due to altered affinity for SDS, which has the effect of retarding their electrophoretic mobility in gels (5, 44).”
Background
Molecular cloning of XTP, a tau-like microtubule-associated protein from Xenopus laevis tadpoles
Olesen, O. F., Kawabata-Fukui, H., Yoshizato, K., & Noro, N. (2002) · Gene · doi:10.1016/s0378-1119(01)00869-1 · Cited by 18
Probing modifications of the neuronal cytoskeleton
Doering, L. C. (1993) · Molecular Neurobiology · doi:10.1007/bf02769179 · Cited by 18
Tangles and Plaques: A deep dive into the pathological hallmarks of Alzheimer’s disease
Vanya, Kumari, S., Bagri, K., & Deshmukh, R. R. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.10.050 · Cited by 18
Membrane estrogen receptor ERα activation improves tau clearance via autophagy induction in a tauopathy cell model
Costa, A. J., Oliveira, R. B., Wachilewski, P., Nishino, M. S., Bassani, T. B., Stilhano, R. S., Cerutti, J. M., Nozima, B. H. N., Porto, C. S., Pereira, G. J. S., et al. (2022) · Brain Research · doi:10.1016/j.brainres.2022.148079 · Cited by 17
Single‐molecule imaging reveals Tau trapping at nanometer‐sized dynamic hot spots near the plasma membrane that persists after microtubule perturbation and cholesterol depletion
Padmanabhan, P., Kneynsberg, A., Cruz, E., Amor, R., Sibarita, J., & Götz, J. (2022) · The EMBO Journal · doi:10.15252/embj.2022111265 · Cited by 15
“Previous studies have shown that different recombinant forms of Tau have different aggregation rates and filament formation capabilities in cell-free conditions (Goedert & Jakes, 1990; King et al , 2000).”
Presence of Phosphorylated Tau Protein in the Skin of Alzheimer´s Disease Patients
Guadalupe, G. (2015) · Journal of Molecular Biomarkers & Diagnosis · doi:10.4172/2155-9929.s6-005 · Cited by 17
“We confirm here by means of Western blot the presence of p-Tau in the skin showing a similar molecular weight as in other organs [20-22].”
Background
Targeting of Disordered Proteins by Small Molecules in Neurodegenerative Diseases
Longhena, F., Spano, P., & Bellucci, A. (2017) · Handbook of experimental pharmacology · doi:10.1007/164_2017_60 · Cited by 17
Synthesis and conformational properties of phosphopeptides related to the human tau protein
Du, J., Li, Y., Ma, Q., Wei, Q., Zhao, Y., Abe, H., Kanazawa, K., Qin, X., Aoyagi, R., Ishizuka, Y., et al. (2005) · Regulatory Peptides · doi:10.1016/j.regpep.2005.03.003 · Cited by 17
Phosphorylation of tau protein in tau-transfected 3T3 cells
Sygowski, L. A., Fieles, A. W., Lo, M. M. S., Scott, C. W., & Caputo, C. B. (1993) · Molecular Brain Research · doi:10.1016/0169-328x(93)90044-p · Cited by 17
Oxidized and phosphorylated synthetic peptides corresponding to the second and third tubulin‐binding repeats of the τ protein reveal structural features of paired helical filament assembly
Hoffmann, R., Dawson, N. F., Wade, J. D., & Ötvös, L. (1997) · Journal of Peptide Research · doi:10.1111/j.1399-3011.1997.tb01178.x · Cited by 17
The big tau splice isoform resists Alzheimer’s-related pathological changesPreprint
Chung, D. C., Deng, X., Yalamanchili, H. K., Revelli, J., Han, A. L., Tadros, B., Richman, R., Dias, M., Naini, F. A., Boeynaems, S., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.30.605685 · Cited by 16
Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies
Davidson, R., Krider, R. I., Borsellino, P., Noorda, K., Alhwayek, G., & Vida, T. A. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45110553 · Cited by 17
“Because the 4R isoforms have an extra one of these binding domains compared to the 3R isoforms, they show a higher afﬁnity to bind microtubules [43].”
Background
Compound heterozygosity of 2 novel MAPT mutations in frontotemporal dementia
Anfossi, M., Vuono, R., Maletta, R., Virdee, K., Mirabelli, M., Colao, R., Puccio, G., Bernardi, L., Frangipane, F., Gallo, M., et al. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.12.013 · Cited by 16
“…a region that has previously been associated with the FTDP-17T phenotype, it is located in the loop and not in the stem outside the binding domain of the U6snRNA and in a sequence unlikely to affect the stabilization of the stem (Goedert and Jakes, 1990; Hutton et al., 1998; Poorkaj et al., 1998).”
Influential
Minimal neuropathologic diagnosis for brain banking in the normal middle-aged and aged brain and in neurodegenerative disorders
Alafuzoff, I. I. (2018) · Handbook of clinical neurology · doi:10.1016/b978-0-444-63639-3.00010-4 · Cited by 15
Novel monoclonal antibodies targeting the microtubule-binding domain of human tau
Croft, C. L., Moore, B. D., Ran, Y., Chakrabarty, P., Levites, Y., Golde, T. E., & Giasson, B. I. (2018) · PLoS ONE · doi:10.1371/journal.pone.0195211 · Cited by 16
Tau-Reactive Endogenous Antibodies: Origin, Functionality, and Implications for the Pathophysiology of Alzheimer’s Disease
Hromádková, L., & Ovsepian, S. V. (2019) · Journal of Immunology Research · doi:10.1155/2019/7406810 · Cited by 17
“In the CNS, tau protein occurs in six isoforms due to alternative splicing [17] and as a natively unfolded protein which is subjected to many posttranslational modifications, mostly phosphorylation [18].”
Expression and purification of amyloid β-protein, tau, and α-synuclein in Escherichia coli: a review
Jia, L., Zhao, W., Wei, W., Guo, X. L., Wang, W., Wang, Y., Sang, J., Lu, F., & Liu, F. (2020) · Critical Reviews in Biotechnology · doi:10.1080/07388551.2020.1742646 · Cited by 16
“Table 3 shows numbers of studies on the expression and purification of tau along with information of the expression host, vector, yield, media, cultivation, purification strategies, etc. Expression and purification of tau without fusion partners Goedert and Jakes [63] expressed and purified six tau isoforms with a hig…”
Method
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Derkinderen, P., Rolli‐Derkinderen, M., Chapelet, G., Neunlist, M., & Noble, W. J. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15320 · Cited by 16
“The various splice combinations of tau are thus abbreviated- 0N3R, 0N4R, 1N3R, 1N4R, 2N3R, 2N4R- encoding six proteins isoforms ranging from 352 to 441 amino acids in length (Goedert & Jakes, 1990) (Figure 3).”
Background
Human Induced Pluripotent Stem Cell Models of Frontotemporal Dementia With Tau Pathology
Kühn, R., Mahajan, A., Canoll, P., & Hargus, G. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.766773 · Cited by 18
“In the healthy adult human brain, these 3R and 4R isoforms appear at equal levels (Kosik et al., 1989; Goedert and Jakes, 1990) but in many patients with FTLD-tau including PSP, CBD, AGD, and GGT and including many patients with MAPT mutations, this ratio is shifted toward 4R isoforms (Goedert and…”
Background
Phosphorylation Pattern of tau Associated with Distinct Changes of the Growth Cone Cytoskeleton
Šimić, G., Diana, A., & Hof, P. R. (2003) · Progress in molecular and subcellular biology · doi:10.1007/978-3-642-55557-2_2 · Cited by 17
Optimization of in vitro conditions to study the arachidonic acid induction of 4R isoforms of the microtubule-associated protein tau
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Ectopic Expression Induces Abnormal Somatodendritic Distribution of Tau in the Mouse Brain
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Analysis of the molecular heterogeneity of the microtubule-associated protein tau by two-dimensional electrophoresis and RT-PCR
Janke, C., Beck, M., Holzer, M., Bigl, V., & Arendt, T. (2000) · Brain Research Protocols · doi:10.1016/s1385-299x(00)00018-0 · Cited by 16
Multiple Forms of Phosphatase from Human Brain: Isolation and Partial Characterization of Affi-Gel Blue Nonbinding Phosphatase Activities
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Authors: Goedert, M., & Jakes, R.
Affiliations: MRC Laboratory of Molecular Biology (GB)
ORCID: Goedert, M.
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 1990-12-01
Volume: 9
Issue: 13
Pages: 4225-4230
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1002/j.1460-2075.1990.tb07870.x
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: The EMBO Journal (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization.

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