α-Synuclein Binds to Tau and Stimulates the Protein Kinase A-catalyzed Tau Phosphorylation of Serine Residues 262 and 356
Open accessAbstract
alpha-Synuclein has been implicated in the pathogenesis of several neurodegenerative disorders based on the direct linking of missense mutations in alpha-synuclein to autosomal dominant Parkinson's disease and its presence in Lewy-like lesions. To gain insight into alpha-synuclein functions, we have investigated whether it binds neuronal proteins and modulates their functional state. The microtubule-associated protein tau was identified as a ligand by alpha-synuclein affinity chromatography of human brain cytosol. Direct binding assays using (125)I-labeled human tau40 demonstrated a reversible binding with a IC(50) about 50 pM. The interacting domains were localized to the C terminus of alpha-synuclein and the microtubule binding region of tau as determined by protein fragmentation and the use of recombinant peptides. High concentrations of tubulin inhibited the binding between tau and alpha-synuclein. Functionally, alpha-synuclein stimulated the protein kinase A-catalyzed phosphorylation of tau serine residues 262 and 356 as determined using a phospho-epitope-specific antibody. We propose that alpha-synuclein modulates the phosphorylation of soluble axonal tau and thereby indirectly affects the stability of axonal microtubules.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
α-synuclein stimulates protein kinase A to catalyse phosphorylation of tau serine residues 262 and 356.
“as a result, α-syn stimulates protein kinase a to catalyse the phosphorylation of tau serine residues 262 and 356 [47].”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [47]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997) · Nature · doi:10.1038/42166 · Cited by 8,382 · see citing works
Self-citationMutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., et al. (1997) · Science · doi:10.1126/science.276.5321.2045 · Cited by 8,240 · see citing works
AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease
Krüger, R., Kuhn, W., Müller, T., Woitalla, D., Graeber, M., Kösel, S., Przuntek, H., Epplen, J. T., Schols, L., & Riess, O. (1998) · Nature Genetics · doi:10.1038/ng0298-106 · Cited by 3,836 · see citing works
Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D., & Crowther, R. A. (1989) · Neuron · doi:10.1016/0896-6273(89)90210-9 · Cited by 2,492 · see citing works
Self-citationSynuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal
Maroteaux, L., Campanelli, J., & Scheller, R. (1988) · Journal of Neuroscience · doi:10.1523/jneurosci.08-08-02804.1988 · Cited by 1,646 · see citing works
(1998) · Europe PMC (PubMed Central) · Cited by 1,594 · see citing works
Stabilization of α-Synuclein Secondary Structure upon Binding to Synthetic Membranes
Davidson, W. S., Jonas, A., Clayton, D. F., & George, J. M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.16.9443 · Cited by 1,588 · see citing works
NACP, A Protein Implicated in Alzheimer's Disease and Learning, Is Natively Unfolded
Weinreb, P. H., Zhen, W., Poon, A. W., Conway, K. A., & Lansbury, P. T. (1996) · Biochemistry · doi:10.1021/bi961799n · Cited by 1,524 · see citing works
Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease.
Uéda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M., Otero, D. A., Kondo, J. D. M., Ihara, Y., & Saitoh, T. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.23.11282 · Cited by 1,469 · see citing works
Iwai, A., Masliah, E., Yoshimoto, M., Ge, N., Flanagan, L., Rohan de Silva, H. A., Kittel, A., & Saitoh, T. (1995) · Neuron · doi:10.1016/0896-6273(95)90302-x · Cited by 1,316 · see citing works
Identification of two distinct synucleins from human brain
Jakes, R., Spillantini, M. G., & Goedert, M. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)00395-5 · Cited by 1,080 · see citing works
Self-citationGoedert, M., Jakes, R., Spillantini, M. G., Hasegawa, M., Smith, M. J., & Crowther, R. A. (1996) · Nature · doi:10.1038/383550a0 · Cited by 1,036 · see citing works
Self-citationGoedert, M., & Jakes, R. (1990) · The EMBO Journal · doi:10.1002/j.1460-2075.1990.tb07870.x · Cited by 929 · see citing works
Self-citationDrewes, G., Ebneth, A., Preuss, U., Mandelkow, E.-M., & Mandelkow, E. (1997) · Cell · doi:10.1016/s0092-8674(00)80208-1 · Cited by 878 · see citing works
George, J. M., Jin, H., Woods, W. S., & Clayton, D. F. (1995) · Neuron · doi:10.1016/0896-6273(95)90040-3 · Cited by 844 · see citing works
Biernat, J., Gustke, N., Drewes, G., Mandelkow, E., & Mandelkow, E. (1993) · Neuron · doi:10.1016/0896-6273(93)90279-z · Cited by 796 · see citing works
Tau protein binds to microtubules through a flexible array of distributed weak sites.
Butner, K. A., & Kirschner, M. W. (1991) · The Journal of cell biology · doi:10.1083/jcb.115.3.717 · Cited by 550 · see citing works
Lippa, C. F., Fujiwara, H., Mann, D. M. A., Giasson, B., Baba, M., Schmidt, M. L., Nee, L. E., O'Connell, B., Pollen, D. A., St. George-Hyslop, P., et al. (1998) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65722-7 · Cited by 533 · see citing works
Binding of α-Synuclein to Brain Vesicles Is Abolished by Familial Parkinson's Disease Mutation
Jensen, P. H., Nielsen, M. S., Jakes, R., Dotti, C. G., & Goedert, M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.41.26292 · Cited by 512 · see citing works
Self-citationThe microtubule binding domain of tau protein
Lee, G., Neve, R. L., & Kosik, K. S. (1989) · Neuron · doi:10.1016/0896-6273(89)90050-0 · Cited by 500 · see citing works
Jenco, J. M., Rawlingson, A., Daniels, B., & Morris, A. J. (1998) · Biochemistry · doi:10.1021/bi972776r · Cited by 431 · see citing works
Role of microtubule-associated proteins in the control of microtubule assembly
Maccioni, R. B., & Cambiazo, V. (1995) · Physiological Reviews · doi:10.1152/physrev.1995.75.4.835 · Cited by 418 · see citing works
Presenilin 1 associates with glycogen synthase kinase-3β and its substrate tau
Takashima, A., Murayama, M., Murayama, O., Kohno, T., Honda, T., Yasutake, K., Nihonmatsu, N., Mercken, M. H., Yamaguchi, H., Sugihara, S., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.16.9637 · Cited by 404 · see citing works
Sontag, E., Nunbhakdi‐Craig, V., Lee, G. S., Bloom, G. S., & Mumby, M. C. (1996) · Neuron · doi:10.1016/s0896-6273(00)80250-0 · Cited by 391 · see citing works
Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing.
Ji, H. W., Liu, Y. E., Jia, T., Wang, M., Liu, J., Xiao, G., Joseph, B. K., Rosen, C. A., & Shi, Y. (1997) · PubMed · Cited by 327 · see citing works
Filamentous nerve cell inclusions in neurodegenerative diseases
Goedert, M., Spillantini, M. G., & Davies, S. W. (1998) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(98)80090-1 · Cited by 260 · see citing works
Withers, G. S., George, J. M., Banker, G. A., & Clayton, D. F. (1997) · Developmental Brain Research · doi:10.1016/s0165-3806(96)00210-6 · Cited by 235 · see citing works
Polarized sorting of glypiated proteins in hippocampal neurons
Dotti, C. G., Parton, R. G., & Simons, K. (1991) · Nature · doi:10.1038/349158a0 · Cited by 230 · see citing works
Irizarry, M. C., Kim, T., McNamara, M. J., Tanzi, R. E., George, J. M., Clayton, D. F., & Hyman, B. T. (1996) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199608000-00004 · Cited by 205 · see citing works
Yoshimoto, M., Iwai, A., Kang, D. E., Otero, D. A., Xia, Y., & Saitoh, T. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9141 · Cited by 202 · see citing works
Alpha synuclein in neurodegenerative disorders: Murderer or accomplice?
Mezey, É., Dehejia, A. M., Harta, G., Papp, M. I., Polymeropoulos, M. H., & Brownstein, M. (1998) · Nature Medicine · doi:10.1038/nm0798-755 · Cited by 185 · see citing works
Identification, localization and characterization of the human γ-synuclein gene
Lavedan, C. N., Leroy, E., Dehejia, A. M., Buchholtz, S. A., Dutra, A., Nussbaum, R. L., & Polymeropoulos, M. H. (1998) · Human Genetics · doi:10.1007/s004390050792 · Cited by 179 · see citing works
Crowther, R. A., Olesen, O. F., Jakes, R., & Goedert, M. (1992) · FEBS Letters · doi:10.1016/0014-5793(92)81094-3 · Cited by 166 · see citing works
Self-citationPurification and characterization of a basic 23 kDa cytosolic protein from bovine brain
Bernier, I., & Jollès, P. (1984) · Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology · doi:10.1016/0167-4838(84)90221-8 · Cited by 160 · see citing works
Litersky, J. M., Johnson, G. V. W., Jakes, R., Goedert, M., Lee, M., & Seubert, P. A. (1996) · Biochemical Journal · doi:10.1042/bj3160655 · Cited by 150 · see citing works
Self-citationProtein Phosphatase 1 Is Targeted to Microtubules by the Microtubule-associated Protein Tau
Liao, H., Li, Y., Brautigan, D. L., & Gundersen, G. G. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.34.21901 · Cited by 145 · see citing works
Jensen, P. H., Højrup, P., Hager, H., Nielsen, M. S., JACOBSEN, L., Olesen, O. F., Gliemann, J., & Jakes, R. (1997) · Biochemical Journal · doi:10.1042/bj3230539 · Cited by 143 · see citing works
Self-citationSchmidt, M. L., Martin, J. A., Lee, V. M. ‐., & Trojanowski, J. Q. (1996) · Acta Neuropathologica · doi:10.1007/s004010050454 · Cited by 140 · see citing works
Localization of the tubulin binding site for tau protein
Serrano, L. G., de Garcini, E. M., HERNÁNDEZ, M. A., & Ávila, J. (1985) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1985.tb09342.x · Cited by 136 · see citing works
Elluru, R. G., Bloom, G. S., & Brady, S. T. (1995) · Molecular Biology of the Cell · doi:10.1091/mbc.6.1.21 · Cited by 119 · see citing works
Shibayama‐Imazu, T., Okahashi, I., Omata, K., Nakajo, S., Ochiai, H., Nakai, Y., Hama, T., Nakamura, Y., & Nakaya, K. (1993) · Brain Research · doi:10.1016/0006-8993(93)90796-p · Cited by 117 · see citing works
Purification and Characterization of a Novel Brain‐Specific 14‐kDa Protein
Nakajo, S., Omata, K., Aiuchi, T., Shibayama, T., Okahashi, I., Ochiai, H., Nakai, Y., Nakaya, K., & Nakamura, Y. (1990) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1990.tb05792.x · Cited by 108 · see citing works
Organization, expression and polymorphism of the human persyn gene
Ninkina, N. N. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.9.1417 · Cited by 107 · see citing works
Peripheral Nervous System-specific Genes Identified by Subtractive cDNA Cloning
Akopian, A. N., & Wood, J. N. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.36.21264 · Cited by 100 · see citing works
The synaptic protein NACP is abnormally expressed during the progression of Alzheimer' s disease
Iwai, A., Masliah, E., Sundsmo, M. P., DeTeresa, R. M., Mallory, M. E., Salmon, D. P., & Saitoh, T. (1996) · Brain Research · doi:10.1016/0006-8993(96)00014-5 · Cited by 52 · see citing works
Jensen, P. H., Jensen, T. G., Laug, W. E., et al. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.43.26892 · Cited by 33 · see citing works
Self-citationGenetic dissection of familial Parkinson's disease
Rieß, O., Jakes, R., & Krüger, R. (1998) · Molecular Medicine Today · doi:10.1016/s1357-4310(98)01343-4 · Cited by 32 · see citing works
Self-citationOlesen, O. F. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)30076-4 · Cited by 13 · see citing works
Flagged first, then by citations
Research works printed but not linked: 4
- Ueda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M., Otero, D. A., Kondo, J., Ihara, Y., and Saitoh, T. (1993) Proc. Natl. Acad. Sci.
- Goslin, K., and Banker, G. (1991) in Culturing Nerve Cells (Banker, G., and Goslin, K., eds) pp. 251-282, MIT Press, Cambridge, MA 28.
- Yoshimoto, M., Iwai, A., Kang, D., Otero, D. A., Xia, Y., and Saitoh, T. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 9141-9145
- Takashima, A., Murayama, M., Murayama, O., Kohno, T., Honda, T., Yasutake, K., Nihonmatsu, N., Mercken, M., Yamaguchi, H., Sugihara, S., and Wolozin, B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 9637-9641
Cited by
Sorted by citations
Dauer, W., & Przedborski, S. (2003) · Neuron · doi:10.1016/s0896-6273(03)00568-3 · Cited by 5,469 · see citing works
-Synuclein in Parkinson's Disease
Stefanis, L. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009399 · Cited by 1,446 · see citing works
Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003 · see citing works
Initiation and Synergistic Fibrillization of Tau and Alpha-Synuclein
Giasson, B. I., Forman, M. S., Higuchi, M., Golbe, L. I., Graves, C. L., Kotzbauer, P. T., Trojanowski, J. Q., & Lee, V. M.-Y. (2003) · Science · doi:10.1126/science.1082324 · Cited by 879 · see citing works
Arendt, T., Stieler, J. T., & Holzer, M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.08.018 · Cited by 609 · see citing works
Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies
Sinsky, J., Pichlerova, K., & Hanes, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179207 · Cited by 220 · see citing works
Arai, Y., Yamazaki, M., Mori, O., Muramatsu, H., Asano, G., & Katayama, Y. (2001) · Brain Research · doi:10.1016/s0006-8993(00)03082-1 · Cited by 173 · see citing works
Wennström, M., Surova, Y., Hall, S., Nilsson, C., Minthon, L., Boström, F., Hansson, O., & Nielsen, H. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053250 · Cited by 141 · see citing works
Could a loss of α‐synuclein function put dopaminergic neurons at risk?
Perez, R. G., & Hastings, T. G. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02423.x · Cited by 133 · see citing works
Axonal degeneration as a therapeutic target in the CNS
Lingor, P., Koch, J. C., Tönges, L., & Bähr, M. (2012) · Cell and Tissue Research · doi:10.1007/s00441-012-1362-3 · Cited by 119 · see citing works
Tau biology, tauopathy, traumatic brain injury, and diagnostic challenges
Castellani, R. J., & Perry, G. (2019) · Journal of Alzheimer’s Disease · doi:10.3233/jad-180721 · Cited by 110 · see citing works
Altered CSF Orexin and α-Synuclein Levels in Dementia Patients
Wennström, M., Londos, E., Minthon, L., & Nielsen, H. M. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2012-111655 · Cited by 104 · see citing works
Azorsa, D. O., Robeson, R. H., Frost, D., hoovet, B. M., Brautigam, G. R., Dickey, C., Beaudry, C., Basu, G. D., Holz, D. R., Hernandez, J. A., et al. (2010) · BMC Genomics · doi:10.1186/1471-2164-11-25 · Cited by 88 · see citing works
Stimulatory effect of <b>α</b>‐synuclein on the tau‐phosphorylation by GSK‐3<b>β</b>
Kawakami, F., Suzuki, M., Shimada, N., Kagiya, G., Ohta, E., Tamura, K., Maruyama, H., & Ichikawa, T. (2011) · The FEBS Journal · doi:10.1111/j.1742-4658.2011.08389.x · Cited by 82 · see citing works
Yang, J., Zhi, W., & Wang, L. (2024) · Molecules · doi:10.3390/molecules29122812 · Cited by 63 · see citing works
- Authors
- Jensen, P. H., Hager, H., Nielsen, M. S., Højrup, P., Gliemann, J., & Jakes, R.
- Affiliations
- Aarhus University (DK)
- University of Southern Denmark (DK)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Jensen, Poul Henning
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-09
- Volume
- 274
- Issue
- 36
- Pages
- 25481-25489
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2016473759
- Cited by
- 377
- References
- 48
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 11 · 2023: 8 · 2022: 13 · 2021: 21 · 2020: 17 · 2019: 15 · 2018: 16 · 2017: 18 · 2016: 12 · 2015: 9 · 2014: 15 · 2013: 17 · 2012: 15
- FWCI
- 10.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, other-oa)
- Funders
- Michaelsen Fonden
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, tau protein, protein-protein binding, protein kinase A, tau phosphorylation, Parkinson's disease, Lewy bodies, microtubule binding, neurodegenerative diseases
- MeSH terms
- Axons, Escherichia coli, Humans, Nerve Tissue Proteins, Neurons, Phosphoproteins, Phosphorylation, Serine, Signal Transduction, tau Proteins, Cyclic AMP-Dependent Protein Kinases, Synucleins, alpha-Synuclein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review