Stimulatory effect of α‐synuclein on the tau‐phosphorylation by GSK‐3 β
Abstract
Hyperphosphorylation of tau protein (tau) causes neurodegenerative diseases such as Alzheimer’s disease (AD). Recent studies of the physiological correlation between tau and α‐synuclein (α‐SN) have demonstrated that: (a) phosphorylated tau is also present in Lewy bodies, which are cytoplasmic inclusions formed by abnormal aggregation of α‐SN; and (b) the neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) increases the phosphorylation of tau as well as the protein level of α‐SN in cultured neuronal cells, and also in mice. However, the molecular mechanism responsible for the α‐SN‐mediated hyperphosphorylation of tau remains to be elucidated. In this in vitro study, we found that: (a) α‐SN directly stimulates the phosphorylation of tau by glycogen synthase kinase‐3β (GSK‐3β), (b) α‐SN forms a heterotrimeric complex with tau and GSK‐3β, and (c) the nonamyloid beta component (NAC) domain and an acidic region of α‐SN are responsible for the stimulation of GSK‐3β‐mediated tau phosphorylation. Thus, it is concluded that α‐SN functions as a connecting mediator for tau and GSK‐3β, resulting in GSK‐3β‐mediated tau phosphorylation. Because the expression of α‐SN is promoted by oxidative stress, the accumulation of α‐SN induced by such stress may directly induce the hyperphosphorylation of tau by GSK‐3β. Furthermore, we found that heat shock protein 70 (Hsp70) suppresses the α‐SN‐induced phosphorylation of tau by GSK‐3β through its direct binding to α‐SN, suggesting that Hsp70 acts as a physiological suppressor of α‐SN‐mediated tau hyperphosphorylation. These results suggest that the cellular level of Hsp70 may be a novel therapeutic target to counteract α‐SN‐mediated tau phosphorylation in the initial stage of neurodegenerative disease. Structured digital abstract GSK3Bphosphorylates GSK3B by protein kinase assay (View interaction) TAU binds to ‐SN by pull down (View interaction) GSK3Bphosphorylates TAU by protein kinase assay (View Interaction: 1, 2, 3, 4) TAU physically interacts with ‐SN and HSP70 by pull down (View interaction) TAU physically interacts with ‐SN and GSK3B by pull down (View interaction) GSK3Bbinds to ‐SN by pull down (View interaction) GSK3B physically interacts with ‐SN and HSP70 by pull down (View interaction) HSP70 binds to ‐SN by pull down (View interaction) GSK3Bphosphorylates Gs by protein kinase assay (View interaction)
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
The αSyn-NAC region can directly mediate GSK3β activity by inducing GSK3β autophosphorylation, leading to GSK3β-mediated tau hyperphosphorylation.
“the αSyn-NAC region can directly mediate the activity of GSK3β by inducing GSK3β autophosphorylation leading to GSK3β-mediated tau-hyperphosphorylation [180].”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [180]
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
Molecular Chaperones in the Cytosol: from Nascent Chain to Folded Protein
Hartl, F. U., & Hayer-Hartl, M. K. (2002) · Science · doi:10.1126/science.1068408 · Cited by 3,335 · 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
Lee, V. M.-Y., Goedert, M., & Trojanowski, J. Q. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1121 · Cited by 2,480 · see citing works
(1998) · Europe PMC (PubMed Central) · Cited by 1,594 · 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
Tau phosphorylation: the therapeutic challenge for neurodegenerative disease
Hanger, D. P., Anderton, B. H., & Noble, W. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.01.003 · Cited by 965 · see citing works
Hanger, D. P., Hughes, K., Woodgett, J. R., Brion, J.-P., & Anderton, B. H. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90774-2 · Cited by 737 · see citing works
Modulation of the glycogen synthase kinase‐3 family by tyrosine phosphorylation.
Hughes, K., Nikolakaki, E., Plyte, S. E., Totty, N. F., & Woodgett, J. R. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05715.x · Cited by 630 · see citing works
Mechanisms of tau-induced neurodegeneration
Iqbal, K., Liu, F., Gong, C.-X., Alonso, A. D. C., & Grundke-Iqbal, I. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0486-3 · Cited by 628 · see citing works
Spira, P. J., Sharpe, D. M., Halliday, G. M., Cavanagh, J., & Nicholson, G. A. (2001) · Annals of Neurology · doi:10.1002/ana.67 · Cited by 628 · 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
Glycogen synthase kinase‐3 and the Alzheimer‐like state of microtubule‐associated protein tau
Mandelkow, E.-M., Drewes, G., Biernat, J., Gustke, N., Van Lint, J., Vandenheede, J. R., & Mandelkow, E. (1992) · FEBS Letters · doi:10.1016/0014-5793(92)81496-9 · Cited by 515 · see citing works
Hsp70 Reduces α-Synuclein Aggregation and Toxicity
Klucken, J., Shin, Y., Masliah, E., Hyman, B. T., & McLean, P. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400255200 · Cited by 509 · see citing works
Colocalization of Tau and Alpha-Synuclein Epitopes in Lewy Bodies
Ishizawa, T., Mattila, P. M., Davies, P., Wang, D., & Dickson, D. W. (2003) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/62.4.389 · Cited by 391 · 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
Hernández, F., Borrell, J., Guaza, C., Avila, J., & Lucas, J. J. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01269.x · Cited by 372 · see citing works
The Synuclein FamilyPreprint
Lavedan, C. N. (1998) · Genome Research · doi:10.1101/gr.8.9.871 · Cited by 321 · see citing works
Khatoon, S., Grundke, I., & Iqbal, K. (1992) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1992.tb09432.x · Cited by 304 · see citing works
Wang, Q. M., Fiol, C. J., DePaoli-Roach, A. A., & Roach, P. J. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36661-9 · Cited by 289 · see citing works
α‐Synuclein contributes to GSK‐3β‐catalyzed Tau phosphorylation in Parkinson's disease models
Duka, T., Duka, V., Joyce, J. N., & Sidhu, A. (2009) · The FASEB Journal · doi:10.1096/fj.08-120410 · Cited by 276 · see citing works
Arima, K., Hirai, S., Sunohara, N., Aoto, K., Izumiyama, Y., Uéda, K., Ikeda, K., & Kawai, M. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01848-x · Cited by 209 · see citing works
Ishiguro, K., Omori, A., Takamatsu, M., Sato, K., Arioka, M., Uchida, T., & Imahori, K. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90839-y · Cited by 151 · see citing works
Developmental expression of α-synuclein in rat hippocampus and cerebral cortex
Petersen, K. L., Olesen, O. F., & Mikkelsen, J. D. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00596-x · Cited by 125 · see citing works
Neuropathology of non-Alzheimer degenerative disorders.
(2009) · PubMed Central · Cited by 117 · see citing works
Hamilton, G., Proitsi, P., Jehu, L., Morgan, A. R., Williams, J. H., O’Donovan, M. C., Owen, M. J., Powell, J. F., & Lovestone, S. (2007) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30503 · Cited by 66 · see citing works
Tissue transglutaminase modulates α‐synuclein oligomerization
Segers‐Nolten, I. M. J., Wilhelmus, M. M. M., Veldhuis, G., et al. (2008) · Protein Science · doi:10.1110/ps.036103.108 · Cited by 60 · see citing works
Kawakami, F., Suzuki, K., & Ohtsuki, K. (2008) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.31.193 · Cited by 23 · see citing works
Self-citationKawakami, F., Yamaguchi, A., Suzuki, K., et al. (2007) · The Journal of Biochemistry · doi:10.1093/jb/mvm228 · Cited by 13 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
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
α-synuclein in the pathophysiology of Alzheimer’s disease
Twohig, D., & Nielsen, H. M. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0320-x · Cited by 374 · see citing works
Role of tau protein in Alzheimer’s disease: The prime pathological player
Muralidar, S., Ambi, S. V., Sekaran, S., Thirumalai, D., & Palaniappan, B. (2020) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2020.07.327 · Cited by 278 · 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
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
The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease
for the Dominantly Inherited Alzheimer Network (DIAN), Twohig, D., Rodriguez-Vieitez, E., Sando, S. B., Berge, G., Lauridsen, C., Møller, I., Grøntvedt, G. R., Bråthen, G., Patra, K., et al. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0624-z · Cited by 68 · see citing works
Tau acts as a mediator for<scp>A</scp>lzheimer's disease‐related synaptic deficits
Liao, D., Miller, E. C., & Teravskis, P. J. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12504 · Cited by 53 · see citing works
- Authors
- Kawakami, F., Suzuki, M., Shimada, N., Kagiya, G., Ohta, E., Tamura, K., Maruyama, H., & Ichikawa, T.
- Affiliations
- Kitasato University (JP)
- Venue
- The FEBS Journal
- Publisher
- Wiley
- Published
- 2011-10-31
- Volume
- 278
- Issue
- 24
- Pages
- 4895-4904
- ISSN
- 1742-464X (ISSN-L)
- 1742-4658
- OpenAlex
- W1579214214
- Cited by
- 82
- References
- 29
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 12 · 2019: 4 · 2018: 6 · 2017: 5 · 2016: 4 · 2015: 2 · 2014: 11 · 2013: 4 · 2012: 5
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- FEBS Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (21591618)
- 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 hyperphosphorylation, glycogen synthase kinase-3β, Lewy bodies, Alzheimer's disease, HSP70, oxidative stress, protein-protein interaction, neurodegeneration, therapeutic target, MPTP, Lewy body pathology
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Humans, Phosphorylation, tau Proteins, HSP70 Heat-Shock Proteins, Glycogen Synthase Kinase 3, alpha-Synuclein, gamma-Synuclein, beta-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
