O-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer's disease
Open accessAbstract
Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains of individuals with Alzheimer's disease (AD) and other tauopathies. Tau pathology is critical to pathogenesis and correlates to the severity of dementia. However, the mechanisms leading to abnormal hyperphosphorylation are unknown. Here, we demonstrate that human brain tau was modified by O-GlcNAcylation, a type of protein O-glycosylation by which the monosaccharide β- N -acetylglucosamine (GlcNAc) attaches to serine/threonine residues via an O-linked glycosidic bond. O-GlcNAcylation regulated phosphorylation of tau in a site-specific manner both in vitro and in vivo . At most of the phosphorylation sites, O-GlcNAcylation negatively regulated tau phosphorylation. In an animal model of starved mice, low glucose uptake/metabolism that mimicked those observed in AD brain produced a decrease in O-GlcNAcylation and consequent hyperphosphorylation of tau at the majority of the phosphorylation sites. The O-GlcNAcylation level in AD brain extracts was decreased as compared to that in controls. These results reveal a mechanism of regulation of tau phosphorylation and suggest that abnormal hyperphosphorylation of tau could result from decreased tau O-GlcNAcylation, which probably is induced by deficient brain glucose uptake/metabolism in AD and other tauopathies.
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A reduction of glucose consumption induces an increase in phospho-Tau and Aβ accumulation.
“a reduction of glucose consumption induces an increase in phospho-Tau and A β accumulation (Fu et al., 2015; Liu et al., 2004).”
From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as Liu et al., 2004
The section on decreased glucose uptake/metabolism reports that starved mice had increased tau phosphorylation. The Discussion does not report that reduced glucose consumption causes Aβ accumulation; instead, it says Aβ peptide can impair glucose uptake and utilization. The Aβ accumulation part of the claim is therefore unsupported by this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measuredReduced tau O-glycosylation could lead to increased phosphorylation, while enhancement of O-glycosylation reduces the extent of tau phosphorylation.
“For example, reduced tau O-glycosylation could lead to increased phosphorylation, while the enhancement of O-glycosylation reduces the extent of tau phosphorylation [43–45].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [43]
A reciprocal relationship exists between O-GlcNAcylation and phosphorylation on tau.
“As discussed above, a reciprocal relationship has been found between O-GlcNAcylation and phosphorylation on tau [43].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [43]
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Cites
Hearing loss and cognitive decline in older adults
Lin, F. R., Yaffe, K., Xia, J., Xue, Q.-L., Harris, T. B., Purchase-Helzner, E., Satterfield, S., Ayonayon, H. N., Ferrucci, L., Simonsick, E. M., et al. (2013) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2013.1868 · Cited by 4,017 · see citing works
Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease
Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T., & Hyman, B. T. (1992) · Neurology · doi:10.1212/wnl.42.3.631 · Cited by 2,668 · 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
Diabetes mellitus and the risk of dementia: The Rotterdam Study
Ott, A., Stolk, R. P., van Harskamp, F., Pols, H. A. P., Hofman, A., & Breteler, M. M. B. (1999) · Neurology · doi:10.1212/wnl.53.9.1937 · Cited by 2,175 · see citing works
Buée, L., Bussière, T., Buée‐Scherrer, V., Delacourte, A., & Hof, P. R. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(00)00019-9 · Cited by 2,007 · see citing works
Microtubule-associated protein tau. A component of Alzheimer paired helical filaments.
Grundke, I., Iqbal, K., Quinlan, M., Tung, Y. C., Zaidi, M. S., & Wisniewski, H. M. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)38495-8 · Cited by 1,780 · see citing works
Self-citationA68: a Major Subunit of Paired Helical Filaments and Derivatized Forms of Normal Tau
Lee, V. M.-Y., Balin, B. J., Otvos, L., & Trojanowski, J. Q. (1991) · Science · doi:10.1126/science.1899488 · Cited by 1,418 · see citing works
Goedert, M., Spillantini, M. G., Cairns, N. J., & Crowther, R. A. (1992) · Neuron · doi:10.1016/0896-6273(92)90117-v · Cited by 1,114 · see citing works
Köpke, E., Tung, Y. C., Shaikh, S., Alonso, A. C., Iqbal, K., & Grundke-Iqbal, I. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80536-5 · Cited by 779 · see citing works
Self-citationDynamic O-Glycosylation of Nuclear and Cytosolic Proteins
Gao, Y., Wells, L., Comer, F. I., Parker, G. J., & Hart, G. W. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010420200 · Cited by 757 · see citing works
Self-citationAlzheimer's β-Amyloid Peptides Compete for Insulin Binding to the Insulin Receptor
Xie, L., Helmerhorst, E., Taddei, K., Plewright, B., van Bronswijk, W., & Martins, R. N. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-10-j0001.2002 · Cited by 542 · see citing works
Monoclonal antibodies identify a group of nuclear pore complex glycoproteins.
Snow, C. M., Senior, A., & Gerace, L. (1987) · The Journal of Cell Biology · doi:10.1083/jcb.104.5.1143 · Cited by 542 · see citing works
Memory improvement following induced hyperinsulinemia in Alzheimer’s disease
Craft, S., Newcomer, J., Kanne, S., Dagogo-Jack, S., Cryer, P., Sheline, Y., Luby, J., Dagogo-Jack, A., & Alderson, A. (1996) · Neurobiology of Aging · doi:10.1016/0197-4580(95)02002-0 · Cited by 538 · see citing works
Phosphorylated Tau Protein Is Integrated into Paired Helical Filaments in Alzheimer's Disease1
Ihara, Y., Nukina, N., Miura, R., & OGAWARA, M. (1986) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a135662 · Cited by 527 · see citing works
Evidence for Genetic Linkage of Alzheimer's Disease to Chromosome 10q
Bertram, L., Blacker, D., Mullin, K., Keeney, D. B., Jones, J., Basu, S., Yhu, S., McInnis, M. G., Go, R. C. P., Vekrellis, K., et al. (2000) · Science · doi:10.1126/science.290.5500.2302 · Cited by 519 · see citing works
DYNAMIC O-LINKED GLYCOSYLATION OF NUCLEAR AND CYTOSKELETAL PROTEINS
Hart, G. W. (1997) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.66.1.315 · Cited by 503 · see citing works
Self-citationGlucose metabolism and insulin receptor signal transduction in Alzheimer disease
Hoyer, S. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.02.049 · Cited by 436 · see citing works
Gong, C.-X., Lidsky, T., Wegiel, J., Zuck, L., Grundke-Iqbal, I., & Iqbal, K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.8.5535 · Cited by 405 · see citing works
Self-citationRiley, K. P., Snowdon, D. A., & Markesbery, W. R. (2002) · Annals of Neurology · doi:10.1002/ana.10161 · Cited by 392 · see citing works
O-Glycosylation of Nuclear and Cytosolic Proteins
Comer, F. I., & Hart, G. W. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.r000010200 · Cited by 361 · see citing works
Self-citationThe Microtubule-associated Protein Tau Is Extensively Modified with O-linked N-acetylglucosamine
Arnold, C. S., Johnson, G. W., Cole, R. N., Dong, D. L.-Y., Lee, M., & Hart, G. W. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.46.28741 · Cited by 361 · see citing works
Self-citationTumor Promotion by Inhibitors of ProteinZ Phosphatases 1 and 2A: The Okadaic Acid Class of Compounds
Fujiki, H., & Suganuma, M. (1993) · Advances in cancer research · doi:10.1016/s0065-230x(08)60958-6 · Cited by 309 · see citing works
Characterization of a Mouse Monoclonal Antibody Specific for O-Linked N-Acetylglucosamine
Comer, F. I., Vosseller, K., Wells, L., Accavitti, M. A., & Hart, G. W. (2001) · Analytical Biochemistry · doi:10.1006/abio.2001.5132 · Cited by 295 · see citing works
Self-citationHaltiwanger, R. S., Grove, K., & Philipsberg, G. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.6.3611 · Cited by 275 · see citing works
Phosphate analysis and dephosphorylation of modified tau associated with paired helical filaments.
Księżak-Reding, H., Liu, W.-K., & Shu, H.-Y. C. (1992) · Brain Research · doi:10.1016/0006-8993(92)91476-u · Cited by 237 · see citing works
Meguro, K., Blaizot, X., Kondoh, Y., Mestric, C. L., Baron, J., & Chavoix, C. (1999) · Brain · doi:10.1093/brain/122.8.1519 · Cited by 228 · see citing works
Niwa, K., Kazama, K., Younkin, S. G., Carlson, G. A., & Iadecola, C. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2001.0460 · Cited by 218 · see citing works
Lefebvre, T., Ferreira, S., Dupont-Wallois, L., Bussière, T., Dupire, M.-J., Delacourte, A., Michalski, J., & Caillet‐Boudin, M. (2003) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(02)00477-4 · Cited by 209 · see citing works
Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK‐3β
Liu, F., Iqbal, K., Grundke, I., & Gong, C. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03487-7 · Cited by 197 · see citing works
Self-citationPlanel, E., Yasutake, K., Fujita, S. C., & Ishiguro, K. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102780200 · Cited by 197 · see citing works
Diminished Glucose Transport in Alzheimer's Disease: Dynamic PET Studies
Jagust, W. J., Seab, J. P., Huesman, R. H., Valk, P. E., Mathis, C. A., Reed, B., Coxson, P. G., & Budinger, T. F. (1991) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.1991.65 · Cited by 187 · see citing works
Cheng, B., & Mattson, M. P. (1992) · Experimental Neurology · doi:10.1016/0014-4886(92)90120-f · Cited by 137 · see citing works
[26] Detection of O-Linked N-acetylglucosamine (O-GlcNAc) on cytoplasmic and nuclear proteins
Roquemore, E. P., Chou, T., & Hart, G. W. (1994) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(94)30028-3 · Cited by 136 · see citing works
Self-citationLiu, F., Zaidi, T., Iqbal, K., Grundke, I., & Gong, C. (2002) · Neuroscience · doi:10.1016/s0306-4522(02)00510-9 · Cited by 106 · see citing works
Self-citationRoos, M. D., Xie, W., Su, K., Clark, J. A., Yang, X., Chin, E., Paterson, A. J., & Kudlow, J. E. (1998) · PubMed · Cited by 81 · see citing works
Dephosphorylation of microtubule‐associated protein tau by protein phosphatase 5
Gong, C., Liu, F., Wu, G., Rossie, S. S., Węgiel, J., Li, L., Grundke, I., & Iqbal, K. (2003) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02147.x · Cited by 81 · see citing works
Self-citationIqbal, K., Alonso, A. D. C., El-Akkad, E., Gong, C., Haque, N., Khatoon, S., Pei, J.-J., Tsujio, I., Wang, J., & Grundke, I. (2002) · Journal of Molecular Neuroscience · doi:10.1007/s12031-002-0017-3 · Cited by 49 · see citing works
Self-citationPrapong, T., Buss, J. E., Hsu, W. H., Heine, P. A., Greenlee, H. W., & Uemura, E. (2002) · Experimental Neurology · doi:10.1006/exnr.2001.7861 · Cited by 43 · see citing works
Blaizot, X., Meguro, K., Millien, I., Baron, J., & Chavoix, C. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-21-09166.2002 · Cited by 26 · see citing works
Zimmer, B., & Kilian, N. (1991) · Taxon · doi:10.1002/j.1996-8175.1991.tb01220.x · Cited by 5 · see citing works
Flagged first, then by citations
1 of the 42 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- [24]Roos, M. D., Xie, W., Su, K., Clark, J. A., Yang, X., Chin, E., Paterson, A. J. & Kudlow, J. E. (1998) Proc. Assoc. Am. Physicians 110, 422-432.
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Tau in physiology and pathology
Wang, Y., & Mandelkow, E. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2015.1 · Cited by 2,251 · see citing works
Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders
Ballatore, C., Lee, V. M.-Y., & Trojanowski, J. Q. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2194 · Cited by 2,174 · see citing works
Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins
Hart, G. W., Housley, M. P., & Slawson, C. (2007) · Nature · doi:10.1038/nature05815 · Cited by 1,418 · see citing works
Self-citationHart, G. W., Slawson, C., Ramirez-Correa, G., & Lagerlof, O. (2011) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060608-102511 · Cited by 1,317 · see citing works
Self-citationTau pathology and neurodegeneration
Spillantini, M. G., & Goedert, M. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70090-5 · Cited by 1,133 · 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
Tau pathology in Alzheimer disease and other tauopathies
Iqbal, K., del C. Alonso, A., Chen, S., Chohan, M. O., El-Akkad, E., Gong, C.-X., Khatoon, S., Li, B., Liu, F., Rahman, A., et al. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2004.09.008 · Cited by 1,037 · see citing works
Tau and neurodegenerative disease: the story so far
Iqbal, K., Liu, F., & Gong, C.-X. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.225 · Cited by 806 · see citing works
Self-citationTherapeutics of Alzheimer's disease: Past, present and future
Anand, R., Gill, K. D., & Mahdi, A. A. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.07.004 · Cited by 748 · see citing works
A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo
Yuzwa, S. A., Macauley, M. S., Heinonen, J. E., Shan, X., Dennis, R. J., He, Y., Whitworth, G. E., Stubbs, K. A., McEachern, E. J., Davies, G. J., et al. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.96 · Cited by 717 · see citing works
History and progress of hypotheses and clinical trials for Alzheimer’s disease
Liu, P.-P., Xie, Y., Meng, X.-Y., & Kang, J.-S. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0063-8 · Cited by 723 · 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
Gong, C., & Iqbal, K. (2008) · Current Medicinal Chemistry · doi:10.2174/092986708785909111 · Cited by 649 · see citing works
Self-citationPost-translational modifications of tau protein: Implications for Alzheimer's disease
Martin, L., Latypova, X., & Terro, F. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2010.12.023 · Cited by 645 · 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
Self-citationIncreasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation
Yuzwa, S. A., Shan, X., Macauley, M. S., Clark, T., Skorobogatko, Y., Vosseller, K., & Vocadlo, D. J. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.797 · Cited by 611 · see citing works
Brain fuel metabolism, aging, and Alzheimer’s disease
Cunnane, S. C., Nugent, S., Roy, M., Courchesne‐Loyer, A., Croteau, É., Tremblay, S., Castellano, A., Pifferi, F., Bocti, C., Paquet, N., et al. (2010) · Nutrition · doi:10.1016/j.nut.2010.07.021 · Cited by 607 · see citing works
Glucose transporters in brain in health and disease
Koepsell, H. (2020) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-020-02441-x · Cited by 558 · see citing works
The utility of ETD mass spectrometry in proteomic analysis
Mikesh, L. M., Ueberheide, B. M., Chi, A., Coon, J. J., Syka, J. E. P., Shabanowitz, J., & Hunt, D. F. (2006) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2006.10.003 · Cited by 535 · see citing works
Wang, J., Xia, Y., Grundke, I., & Iqbal, K. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129031 · Cited by 530 · see citing works
Self-citationGlycosylation: mechanisms, biological functions and clinical implications
He, M., Zhou, X., & Wang, X. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01886-1 · Cited by 542 · see citing works
Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes
Liu, Y. M., Liu, F., Grundke, I., Iqbal, K., & Gong, C. (2011) · The Journal of Pathology · doi:10.1002/path.2912 · Cited by 505 · see citing works
Self-citationTau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation
Chen, Y., & Yu, Y. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02853-3 · Cited by 516 · see citing works
“As discussed above, a reciprocal relationship has been found between O-GlcNAcylation and phosphorylation on tau [43].”
BackgroundBlázquez, E., Velázquez, E., Hurtado-Carneiro, V., & Ruiz-Albusac, J. M. (2014) · Frontiers in Endocrinology · doi:10.3389/fendo.2014.00161 · Cited by 502 · see citing works
Morris, M., Knudsen, G. M., Maeda, S., Trinidad, J. C., Ioanoviciu, A., Burlingame, A. L., & Mucke, L. (2015) · Nature Neuroscience · doi:10.1038/nn.4067 · Cited by 472 · see citing works
The role of tau in neurodegeneration
Gendron, T. F., & Petrucelli, L. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-13 · Cited by 478 · see citing works
The Hexosamine Signaling Pathway: Deciphering the "O-GlcNAc Code"
Love, D. C., & Hanover, J. A. (2005) · Science s STKE · doi:10.1126/stke.3122005re13 · Cited by 462 · see citing works
Structure of human O-GlcNAc transferase and its complex with a peptide substrate
Lazarus, M. B., Nam, Y., Jiang, J., Piotr Sliz, A., & Walker, S. (2011) · Nature · doi:10.1038/nature09638 · Cited by 459 · see citing works
Liu, F., Shi, J., Tanimukai, H., Gu, J., Gu, J., Grundke-Iqbal, I., Iqbal, K., & Gong, C.-X. (2009) · Brain · doi:10.1093/brain/awp099 · Cited by 439 · see citing works
Self-citationZhong, Q., Xiao, X., Qiu, Y., Xu, Z., Chen, C., Chong, B., Zhao, X., Hai, S., Li, S., An, Z., et al. (2023) · MedComm · doi:10.1002/mco2.261 · Cited by 442 · see citing works
Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies
Brunden, K. R., Trojanowski, J. Q., & Lee, V. M.-Y. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2959 · Cited by 440 · see citing works
Glial contributions to neurodegeneration in tauopathies
Leyns, C. E. G., & Holtzman, D. M. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0192-x · Cited by 409 · see citing works
Post-translational modifications of tau protein in Alzheimer’s disease
Gong, C.-X., Liu, F., Grundke-Iqbal, I., & Iqbal, K. (2005) · Journal of Neural Transmission · doi:10.1007/s00702-004-0221-0 · Cited by 437 · see citing works
Self-citationTrinidad, J. C., Barkan, D. T., Gulledge, B. F., Thalhammer, A., Šali, A., Schoepfer, R., & Burlingame, A. L. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.o112.018366 · Cited by 426 · 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
Self-citationCaldwell, S. A., Jackson, S. R., Shahriari, K. S., Lynch, T. P., Sethi, G., Walker, S., Vosseller, K., & Reginato, M. J. (2010) · Oncogene · doi:10.1038/onc.2010.41 · Cited by 397 · see citing works
Liu, Y. M., Liu, F., Iqbal, K., Grundke, I., & Gong, C. (2008) · FEBS Letters · doi:10.1016/j.febslet.2007.12.035 · Cited by 396 · see citing works
Self-citationCell signaling, the essential role of O-GlcNAc
Zachara, N. E., & Hart, G. W. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2006.04.007 · Cited by 386 · see citing works
O-GlcNAcase Uses Substrate-assisted Catalysis
Macauley, M. S., Whitworth, G. E., Debowski, A. W., Chin, D., & Vocadlo, D. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413819200 · Cited by 378 · see citing works
Protein homeostasis and aging in neurodegeneration
Douglas, P. M., & Dillin, A. G. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.201005144 · Cited by 372 · see citing works
Tau-targeting therapies for Alzheimer disease: Current status and future directions
Congdon, E. E., Ji, C., Tetlow, A. M., Jiang, Y., & Sigurdsson, E. M. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00883-2 · Cited by 371 · see citing works
Alquezar, C., Arya, S., & Kao, A. W. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2020.595532 · Cited by 367 · see citing works
Role of O -linked N -acetylglucosamine protein modification in cellular (patho)physiology
Chatham, J. C., Zhang, J., & Wende, A. R. (2020) · Physiological Reviews · doi:10.1152/physrev.00043.2019 · Cited by 359 · see citing works
Nutrient regulation of signaling and transcription
Hart, G. W. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.aw119.003226 · Cited by 346 · see citing works
Self-citationVosseller, K., Trinidad, J. C., Chalkley, R. J., Specht, C. G., Thalhammer, A., Lynn, A. J., Snedecor, J., Guan, S., Medzihradszky, K. F., Maltby, D. A., et al. (2006) · Molecular & Cellular Proteomics · doi:10.1074/mcp.t500040-mcp200 · Cited by 346 · see citing works
Probing the dynamics of O-GlcNAc glycosylation in the brain using quantitative proteomics
Khidekel, N., Ficarro, S. B., Clark, P. M., Bryan, M. C., Swaney, D. L., Rexach, J. E., Sun, Y. E., Coon, J. J., Peters, E. C., & Hsieh‐Wilson, L. C. (2007) · Nature Chemical Biology · doi:10.1038/nchembio881 · Cited by 339 · see citing works
Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells
Gloster, T. M., Zandberg, W. F., Heinonen, J. E., Shen, D. L., Deng, L., & Vocadlo, D. J. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.520 · Cited by 336 · see citing works
Wang, Z., Guček, M., & Hart, G. W. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806216105 · Cited by 328 · see citing works
Self-citationThe role of protein glycosylation in Alzheimer disease
Schedin‐Weiss, S., Winblad, B. G., & Tjernberg, L. O. (2013) · FEBS Journal · doi:10.1111/febs.12590 · Cited by 316 · see citing works
O-GlcNAc Cycling: A Link Between Metabolism and Chronic Disease
Bond, M. R., & Hanover, J. A. (2013) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071812-161240 · Cited by 316 · see citing works
Marotta, N. P., Lin, Y., Lewis, Y. E., Ambroso, M. R., Zaro, B. W., Roth, M. T., Arnold, D. B., Langen, R., & Pratt, M. R. (2015) · Nature Chemistry · doi:10.1038/nchem.2361 · Cited by 303 · see citing works
Zeidan, Q., & Hart, G. W. (2009) · Journal of Cell Science · doi:10.1242/jcs.053678 · Cited by 299 · see citing works
Self-citationThe role of glucose transporters in brain disease: Diabetes and Alzheimer’s disease
Shah, K., DeSilva, S., & Abbruscato, T. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms131012629 · Cited by 288 · see citing works
The Emerging Link between O-GlcNAc and Alzheimer Disease
Zhu, Y., Shan, X., Yuzwa, S. A., & Vocadlo, D. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.601351 · Cited by 267 · see citing works
Alzheimer-Like Changes in Rat Models of Spontaneous Diabetes
Li, Z.-G., Zhang, W., & Sima, A. A. F. (2007) · Diabetes · doi:10.2337/db07-0171 · Cited by 265 · see citing works
RNA granules: The good, the bad and the ugly
Thomas, M. G., Loschi, M., Desbats, M. A., & Boccaccio, G. L. (2010) · Cellular Signalling · doi:10.1016/j.cellsig.2010.08.011 · Cited by 262 · see citing works
Wang, Z., Udeshi, N. D., O’Malley, M. M., Shabanowitz, J., Hunt, D. F., & Hart, G. W. (2009) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m900268-mcp200 · Cited by 261 · see citing works
Self-citationDiabetes and Alzheimer’s disease crosstalk
Baglietto‐Vargas, D., Shi, J. J., Yaeger, D. M., Ager, R. R., & LaFerla, F. M. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.03.005 · Cited by 254 · see citing works
O -GlcNAc modification in diabetes and Alzheimer's disease
Dias, W. B., & Hart, G. W. (2007) · Molecular BioSystems · doi:10.1039/b704905f · Cited by 250 · see citing works
Self-citationTau Proteins and Tauopathies in Alzheimer’s Disease
Chong, F. P., Ng, K. Y., Koh, R. Y., & Chye, S. M. (2018) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-017-0574-1 · Cited by 248 · see citing works
Yuzwa, S. A., & Vocadlo, D. J. (2014) · Chemical Society Reviews · doi:10.1039/c4cs00038b · Cited by 247 · see citing works
Tau in neurodegenerative disease
Gao, Y.-L., Wang, N., Sun, F.-R., Cao, X.-P., Zhang, W., & Yu, J.-T. (2018) · Annals of Translational Medicine · doi:10.21037/atm.2018.04.23 · Cited by 222 · 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
The Association of Tau With Mitochondrial Dysfunction in Alzheimer’s Disease
Cheng, Y., & Bai, F. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00163 · Cited by 239 · see citing works
Levine, P. M., Galesic, A., Balana, A. T., Mahul‐Mellier, A., Navarro, M. X., Leon, C. A. D., Lashuel, H. A., & Pratt, M. R. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1808845116 · Cited by 240 · see citing works
Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention
Iqbal, K., & Grundke, I. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00225.x · Cited by 238 · see citing works
Self-citationInsulin Dysfunction InducesIn VivoTau Hyperphosphorylation through Distinct Mechanisms
Planel, E., Tatebayashi, Y., Miyasaka, T., Liu, L., Wang, L., Herman, M., Yu, W. H., Luchsinger, J. A., Wadzinski, B. E., Duff, K., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.3949-07.2007 · Cited by 238 · see citing works
Deng, Y., Li, B., Liu, Y. M., Iqbal, K., Grundke, I., & Gong, C. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.090157 · Cited by 233 · see citing works
Self-citationCheung, W. D., & Hart, G. W. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801222200 · Cited by 233 · see citing works
Self-citationRösler, T. W., Marvian, A. T., Brendel, M., Nykänen, N.-P., Höllerhage, M., Schwarz, S. C., Hopfner, F., Koeglsperger, T., Respondek, G., Schweyer, K., et al. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.101644 · Cited by 219 · 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
Wang, Z., Pandey, A., & Hart, G. W. (2007) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m600453-mcp200 · Cited by 216 · see citing works
Self-citationGlcNAcylation Plays an Essential Role in Breast Cancer Metastasis
Gu, Y., Mi, W., Ge, Y., Liu, H., Fan, Q., Han, C., Yang, J., Han, F., Lu, X., & Yu, W. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-1887 · Cited by 215 · see citing works
Loss of <i>O</i> -GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration
Wang, A. C., Jensen, E. H., Rexach, J. E., Vinters, H. V., & Hsieh-Wilson, L. C. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1606899113 · Cited by 211 · see citing works
Zaro, B. W., Yang, Y., Hang, H. C., & Pratt, M. R. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102458108 · Cited by 209 · see citing works
Liu, F., Li, B., Tung, E., Grundke‐Iqbal, I., Iqbal, K., & Gong, C. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05955.x · Cited by 208 · see citing works
Self-citationUpdates in Alzheimer's disease: from basic research to diagnosis and therapies
Liu, E., Zhang, Y., & Wang, J. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00432-x · Cited by 220 · see citing works
Lima, J. E. B. F., Moreira, N. C. S., & Sakamoto-Hojo, E. T. (2022) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2021.503437 · Cited by 203 · see citing works
Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation
Rexach, J. E., Clark, P. M., Mason, D. E., Neve, R. L., Peters, E. C., & Hsieh‐Wilson, L. C. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.770 · Cited by 199 · see citing works
Tapia‐Rojas, C., Cabezas-Opazo, F., Deaton, C. A., Vergara, E. H., Johnson, G. V. W., & Quintanilla, R. A. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.12.005 · Cited by 195 · see citing works
SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases
Manjula, R., Anuja, K., & Alcain, F. J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.585821 · Cited by 193 · see citing works
Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology
Gloster, T. M., & Vocadlo, D. J. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.1029 · Cited by 196 · see citing works
Tau-Centric targets and drugs in clinical development for the treatment of alzheimer's disease
Panza, F., Solfrizzi, V., Seripa, D., Imbimbo, B. P., Lozupone, M., Santamato, A., Zecca, C., Barulli, M. R., Bellomo, A., Pilotto, A., et al. (2016) · BioMed Research International · doi:10.1155/2016/3245935 · Cited by 195 · see citing works
Liu, Y. M., Liu, F., Grundke, I., Iqbal, K., & Gong, C. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06320.x · Cited by 193 · see citing works
Self-citationShi, J., Zhang, T., Zhou, C., Chohan, M. O., Gu, X., Węgiel, J., Zhou, J., Hwang, Y., Iqbal, K., Grundke, I., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802645200 · Cited by 179 · see citing works
Self-citationFrom Chronic Cerebral Hypoperfusion to Alzheimer-Like Brain Pathology and Neurodegeneration
Zhao, Y., & Gong, C.-X. (2015) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-014-0127-9 · Cited by 180 · see citing works
Self-citationInsulin in the nervous system and the mind: Functions in metabolism, memory, and mood
Lee, S.-H., Zabolotny, J. M., Huang, H., Lee, H., & Kim, Y.-B. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.06.011 · Cited by 176 · see citing works
The Chemical Neurobiology of Carbohydrates
Murrey, H. E., & Hsieh‐Wilson, L. C. (2008) · Chemical Reviews · doi:10.1021/cr078215f · Cited by 174 · see citing works
Analytical and Biochemical Perspectives of Protein O-GlcNAcylation
Ma, J., Wu, C., & Hart, G. W. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c00884 · Cited by 171 · see citing works
Self-citationZhu, Q., Zhou, L., Yang, Z., Lai, M.-C., Xie, H., Wu, L., Xing, C., Zhang, F., & Zheng, S. (2011) · Medical Oncology · doi:10.1007/s12032-011-9912-1 · Cited by 168 · see citing works
Site‐specific interplay between O‐GlcNAcylation and phosphorylation in cellular regulation
Hu, P., Shimoji, S., & Hart, G. W. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.04.044 · Cited by 167 · see citing works
Self-citationLimorenko, G., & Lashuel, H. A. (2021) · Chemical Society Reviews · doi:10.1039/d1cs00127b · Cited by 162 · see citing works
Amyloidogenesis of Tau protein
Niżyński, B., Dzwolak, W., & Nieznański, K. (2017) · Protein Science · doi:10.1002/pro.3275 · Cited by 157 · see citing works
Roles of O-GlcNAc in chronic diseases of aging
Banerjee, P. S., Lagerlöf, O., & Hart, G. W. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2016.05.005 · Cited by 157 · see citing works
Self-citationYuzwa, S. A., Shan, X., Jones, B. A., Zhao, G., Woodward, M. L., Li, X., Zhu, Y., McEachern, E. J., Silverman, M. A., Watson, N. V., et al. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-42 · Cited by 151 · see citing works
Self-citationPKA modulates GSK‐3β‐ and cdk5‐catalyzed phosphorylation of tau in site‐ and kinase‐specific manners
Liu, F., Liang, Z., Shi, J., Yin, D., El-Akkad, E., Grundke, I., Iqbal, K., & Gong, C. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.10.033 · Cited by 149 · see citing works
Self-citationMillan, M. J. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.004 · Cited by 146 · see citing works
Yuzwa, S. A., Cheung, A. H., Okon, M., McIntosh, L. P., & Vocadlo, D. J. (2014) · Journal of Molecular Biology · doi:10.1016/j.jmb.2014.01.004 · Cited by 144 · see citing works
Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis
Groves, J. A., Lee, A., Yildirir, G., & Zachara, N. E. (2013) · Cell Stress and Chaperones · doi:10.1007/s12192-013-0426-y · Cited by 143 · see citing works
O-GlcNAcylation in health and neurodegenerative diseases
Lee, B. E., Suh, P., & Kim, J. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00709-5 · Cited by 143 · see citing works
- Authors
- Liu, F., Iqbal, K., Grundke-Iqbal, I., Hart, G. W., & Gong, C.-X.
- Affiliations
- Johns Hopkins University (US)
- Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314; and Department of Biological Chemistry, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205
- Corresponding author
- Gong, Cheng-Xin
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-07-12
- Volume
- 101
- Issue
- 29
- Pages
- 10804-10809
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC490015
- OpenAlex
- W2164029759
- Cited by
- 775
- References
- 42
- Citations by year
- 2026: 29 · 2025: 50 · 2024: 38 · 2023: 36 · 2022: 44 · 2021: 63 · 2020: 57 · 2019: 38 · 2018: 46 · 2017: 45 · 2016: 33 · 2015: 23 · 2014: 36 · 2013: 24 · 2012: 35
- FWCI
- 10.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Nanjing Medical University
- National Institutes of Health (HD13563)
- National Institute on Aging (AG19158, R01AG019158, AG16760, R01AG016760)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD013563, HD13563)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- O-GlcNAcylation, tau protein, tau hyperphosphorylation, Alzheimer's disease, tauopathy, neurofibrillary tangles, O-glycosylation, glucose metabolism, brain glucose uptake
- MeSH terms
- Acetylglucosamine, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Female, Glycosylation, Humans, Male, Mice, Inbred C57BL, Middle Aged, Phosphorylation, Starvation, PC12 Cells, tau Proteins, Rats, Wistar, Mice, Rats, In Vitro Techniques
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