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Tau Phosphorylation

  • Jesús Avila
  • Félix Hernández
Chapter
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 3)

Abstract

Tau protein is a brain microtubule–associated protein having 79 putative phosphorylatable sites that could be modified by serine/threonine protein kinases. This phosphorylation can be divided in two types, depending whether the modified residue is phosphorylated by proline-directed or by non-proline-directed protein kinases. In neurodegenerative processes (tauopathies), tau is mainly (but not only) modified by a proline-directed protein kinase, glycogen synthase kinase 3 (GSK3). In this chapter, we will review that phosphorylation at serine and threonine residues, the modification that can take place at tyrosine residues, and the dephosphorylation of the modified residues by tau phosphatases. In addition, we will comment on the toxicity of phosphotau in disorders such as Alzheimer’s disease and the development of possible therapies to prevent tau phosphorylation.

Keywords

Alzheimer’s disease Tau phosphorylation GSK3 

References

  1. Alonso AC, Grundke-Iqbal I, Iqbal K (1996) Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med 2:783–787CrossRefPubMedGoogle Scholar
  2. Alonso AC, Li B, Grundke-Iqbal I, Iqbal K (2008) Mechanism of tau-induced neurodegeneration in Alzheimer disease and related tauopathies. Curr Alzheimer Res 5:375–384CrossRefPubMedGoogle Scholar
  3. Arrasate M, Perez M, Avila J (2000) Tau dephosphorylation at tau-1 site correlates with its association to cell membrane. Neurochem Res 25:43–50CrossRefPubMedGoogle Scholar
  4. Atlante A, Amadoro G, Bobba A, de Bari L, Corsetti V, Pappalardo G, Marra E, Calissano P, Passarella S (2008) A peptide containing residues 26–44 of tau protein impairs mitochondrial oxidative phosphorylation acting at the level of the adenine nucleotide translocator. Biochim Biophys Acta 1777:1289–1300CrossRefPubMedGoogle Scholar
  5. Avila J, Lucas JJ, Perez M, Hernandez F (2004) Role of tau protein in both physiological and pathological conditions. Physiol Rev 84:361–384CrossRefPubMedGoogle Scholar
  6. Bhat R, Xue Y, Berg S, Hellberg S, Ormo M, Nilsson Y, Radesater AC, Jerning E, Markgren PO, Borgegard T, Nylof M, Gimenez-Cassina A, Hernandez F, Lucas JJ, Diaz-Nido J, Avila J (2003) Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J Biol Chem 278:45937–45945CrossRefPubMedGoogle Scholar
  7. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259CrossRefPubMedGoogle Scholar
  8. Brandt R, Leger J, Lee G (1995) Interaction of tau with the neural plasma membrane mediated by tau’s amino-terminal projection domain. J Cell Biol 131:1327–1340CrossRefPubMedGoogle Scholar
  9. Brandt R, Hundelt M, Shahani N (2005) Tau alteration and neuronal degeneration in tauopathies: mechanisms and models. Biochim Biophys Acta 1739:331–354PubMedGoogle Scholar
  10. Busceti CL, Biagioni F, Riozzi B, Battaglia G, Storto M, Cinque C, Molinaro G, Gradini R, Caricasole A, Canudas AM, Bruno V, Nicoletti F, Fornai F (2008) Enhanced tau phosphorylation in the hippocampus of mice treated with 3,4-methylenedioxymethamphetamine (“Ecstasy”). J Neurosci 28:3234–3245CrossRefPubMedGoogle Scholar
  11. Chen S, Li B, Grundke-Iqbal I, Iqbal K (2008) I1PP2A affects tau phosphorylation via association with the catalytic subunit of protein phosphatase 2A. J Biol Chem 283:10513–10521CrossRefPubMedGoogle Scholar
  12. Cleveland DW, Hwo SY, Kirschner MW (1977) Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol 116:207–225CrossRefPubMedGoogle Scholar
  13. Cohen P (1989) The structure and regulation of protein phosphatases. Annu Rev Biochem 58:453–508CrossRefPubMedGoogle Scholar
  14. Delacourte A, David JP, Sergeant N, Buee L, Wattez A, Vermersch P, Ghozali F, Fallet-Bianco C, Pasquier F, Lebert F, Petit H, Di Menza C (1999) The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology 52:1158–1165PubMedGoogle Scholar
  15. Derkinderen P, Scales TM, Hanger DP, Leung KY, Byers HL, Ward MA, Lenz C, Price C, Bird IN, Perera T, Kellie S, Williamson R, Noble W, Van Etten RA, Leroy K, Brion JP, Reynolds CH, Anderton BH (2005) Tyrosine 394 is phosphorylated in Alzheimer’s paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase. J Neurosci 25:6584–6593CrossRefPubMedGoogle Scholar
  16. Dotti CG, Banker GA, Binder LI (1987) The expression and distribution of the microtubule-associated proteins tau and microtubule-associated protein 2 in hippocampal neurons in the rat in situ and in cell culture. Neuroscience 23:121–130CrossRefPubMedGoogle Scholar
  17. Drewes G, Mandelkow EM, Baumann K, Goris J, Merlevede W, Mandelkow E (1993) Dephosphorylation of tau protein and Alzheimer paired helical filaments by calcineurin and phosphatase-2A. FEBS Lett 336:425–432CrossRefPubMedGoogle Scholar
  18. Engel T, Hernandez F, Avila J, Lucas JJ (2006a) Full reversal of Alzheimer’s disease-like phenotype in a mouse model with conditional overexpression of glycogen synthase kinase-3. J Neurosci 26:5083–5090CrossRefPubMedGoogle Scholar
  19. Engel T, Lucas JJ, Gomez-Ramos P, Moran MA, Avila J, Hernandez F (2006b) Cooexpression of FTDP-17 tau and GSK-3beta in transgenic mice induce tau polymerization and neurodegeneration. Neurobiol Aging 27:1258–1268CrossRefPubMedGoogle Scholar
  20. Fellous A, Francon J, Lennon AM, Nunez J (1977) Microtubule assembly in vitro. Purification of assembly-promoting factors. Eur J Biochem 78:167–174CrossRefPubMedGoogle Scholar
  21. Goedert M, Satumtira S, Jakes R, Smith MJ, Kamibayashi C, White CL 3rd, Sontag E (2000) Reduced binding of protein phosphatase 2A to tau protein with frontotemporal dementia and parkinsonism linked to chromosome 17 mutations. J Neurochem 75:2155–2162CrossRefPubMedGoogle Scholar
  22. Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA (1989) Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J 8:393–399PubMedGoogle Scholar
  23. Gomez-Ramos A, Diaz-Hernandez M, Rubio A, Miras-Portugal MT, Avila J (2008) Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol Cell Neurosci 37:673–681CrossRefPubMedGoogle Scholar
  24. Gong CX, Grundke-Iqbal I, Damuni Z, Iqbal K (1994a) Dephosphorylation of microtubule-associated protein tau by protein phosphatase-1 and -2C and its implication in Alzheimer disease. FEBS Lett 341:94–98CrossRefPubMedGoogle Scholar
  25. Gong CX, Grundke-Iqbal I, Iqbal K (1994b) Dephosphorylation of Alzheimer’s disease abnormally phosphorylated tau by protein phosphatase-2A. Neuroscience 61:765–772CrossRefPubMedGoogle Scholar
  26. Goni-Oliver P, Lucas JJ, Avila J, Hernandez F (2007) N-terminal cleavage of GSK-3 by calpain: a new form of GSK-3 regulation. J Biol Chem 282:22406–22413CrossRefPubMedGoogle Scholar
  27. Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM (2008) Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci 28:11500–11510CrossRefPubMedGoogle Scholar
  28. Greenwood JA, Johnson GV (1995) Localization and in situ phosphorylation state of nuclear tau. Exp Cell Res 220:332–337CrossRefPubMedGoogle Scholar
  29. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917CrossRefPubMedGoogle Scholar
  30. Inoue M, Hirata A, Tainaka K, Morii T, Konno T (2008) Charge-pairing mechanism of phosphorylation effect upon amyloid fibrillation of human tau core peptide. Biochemistry 47:11847–11857CrossRefPubMedGoogle Scholar
  31. Ishiguro K, Kobayashi S, Omori A, Takamatsu M, Yonekura S, Anzai K, Imahori K, Uchida T (1994) Identification of the 23 kDa subunit of tau protein kinase II as a putative activator of cdk5 in bovine brain. FEBS Lett 342:203–208CrossRefPubMedGoogle Scholar
  32. Ishiguro K, Shiratsuchi A, Sato S, Omori A, Arioka M, Kobayashi S, Uchida T, Imahori K (1993) Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett 325:167–172CrossRefPubMedGoogle Scholar
  33. Ishihara T, Zhang B, Higuchi M, Yoshiyama Y, Trojanowski JQ, Lee VM (2001) Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice. Am J Pathol 158:555–562CrossRefPubMedGoogle Scholar
  34. Janssens V, Goris J (2001) Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353:417–439CrossRefPubMedGoogle Scholar
  35. Kimura T, Yamashita S, Fukuda T, Park JM, Murayama M, Mizoroki T, Yoshiike Y, Sahara N, Takashima A (2007) Hyperphosphorylated tau in parahippocampal cortex impairs place learning in aged mice expressing wild-type human tau. EMBO J 26:5143–5152CrossRefPubMedGoogle Scholar
  36. Kimura T, Fukuda T, Sahara N, Yamashita S, Murayama M, Mizoroki T, Yoshiike Y, Lee B, Sotiropoulos I, Maeda S, Takashima A (2010) Aggregation of detergent-insoluble tau is involved in neuronal loss but not in synaptic loss. J Biol Chem 285:38692–38699CrossRefPubMedGoogle Scholar
  37. Kosik KS, Orecchio LD, Bakalis S, Neve RL (1989) Developmentally regulated expression of specific tau sequences. Neuron 2:1389–1397CrossRefPubMedGoogle Scholar
  38. Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow EM, Eisenbrand G, Meijer L (2001) Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer’s disease. A property common to most cyclin-dependent kinase inhibitors? J Biol Chem 276:251–260CrossRefPubMedGoogle Scholar
  39. Lee G, Cowan N, Kirschner M (1988) The primary structure and heterogeneity of tau protein from mouse brain. Science 239:285–288CrossRefPubMedGoogle Scholar
  40. Lee G, Thangavel R, Sharma VM, Litersky JM, Bhaskar K, Fang SM, Do LH, Andreadis A, Van Hoesen G, Ksiezak-Reding H (2004) Phosphorylation of tau by fyn: implications for Alzheimer’s disease. J Neurosci 24:2304–2312CrossRefPubMedGoogle Scholar
  41. Leost M, Schultz C, Link A, Wu YZ, Biernat J, Mandelkow EM, Bibb JA, Snyder GL, Greengard P, Zaharevitz DW, Gussio R, Senderowicz AM, Sausville EA, Kunick C, Meijer L (2000) Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25. Eur J Biochem 267:5983–5994CrossRefPubMedGoogle Scholar
  42. Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP (1999) The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399:784–788CrossRefPubMedGoogle Scholar
  43. Magnani E, Fan J, Gasparini L, Golding M, Williams M, Schiavo G, Goedert M, Amos LA, Spillantini MG (2007) Interaction of tau protein with the dynactin complex. EMBO J 26:4546–4554CrossRefPubMedGoogle Scholar
  44. Martinez A, Alonso M, Castro A, Perez C, Moreno FJ (2002) First non-ATP competitive glycogen synthase kinase 3 beta (GSK-3beta) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer’s disease. J Med Chem 45:1292–1299CrossRefPubMedGoogle Scholar
  45. Mawal-Dewan M, Henley J, Van de Voorde A, Trojanowski JQ, Lee VM (1994) The phosphorylation state of tau in the developing rat brain is regulated by phosphoprotein phosphatases. J Biol Chem 269:30981–30987PubMedGoogle Scholar
  46. Neve RL, Harris P, Kosik KS, Kurnit DM, Donlon TA (1986) Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. Brain Res 387:271–280PubMedGoogle Scholar
  47. Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L, LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, Duff K (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA 102:6990–6995CrossRefPubMedGoogle Scholar
  48. Ojala JO, Sutinen EM, Salminen A, Pirttila T (2008) Interleukin-18 increases expression of kinases involved in tau phosphorylation in SH-SY5Y neuroblastoma cells. J Neuroimmunol 205:86–93CrossRefPubMedGoogle Scholar
  49. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615–622CrossRefPubMedGoogle Scholar
  50. Perez M, Cuadros R, Smith MA, Perry G, Avila J (2000) Phosphorylated, but not native, tau protein assembles following reaction with the lipid peroxidation product, 4-hydroxy-2-nonenal. FEBS Lett 486:270–274CrossRefPubMedGoogle Scholar
  51. Perez M, Hernandez F, Gomez-Ramos A, Smith M, Perry G, Avila J (2002) Formation of aberrant phosphotau fibrillar polymers in neural cultured cells. Eur J Biochem 269:1484–1489CrossRefPubMedGoogle Scholar
  52. Perez M, Hernandez F, Lim F, Diaz-Nido J, Avila J (2003) Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J Alzheimers Dis 5:301–308PubMedGoogle Scholar
  53. Price DL, Sisodia SS (1998) Mutant genes in familial Alzheimer’s disease and transgenic models. Annu Rev Neurosci 21:479–505CrossRefPubMedGoogle Scholar
  54. Ramesh Babu J, Lamar Seibenhener M, Peng J, Strom AL, Kemppainen R, Cox N, Zhu H, Wooten MC, Diaz-Meco MT, Moscat J, Wooten MW (2008) Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration. J Neurochem 106:107–120CrossRefPubMedGoogle Scholar
  55. Rankin CA, Sun Q, Gamblin TC (2008) Pre-assembled tau filaments phosphorylated by GSK-3b form large tangle-like structures. Neurobiol Dis 31:368–377CrossRefPubMedGoogle Scholar
  56. Reynolds CH, Garwood CJ, Wray S, Price C, Kellie S, Perera T, Zvelebil M, Yang A, Sheppard PW, Varndell IM, Hanger DP, Anderton BH (2008) Phosphorylation regulates tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cgamma1, Grb2, and Src family kinases. J Biol Chem 283:18177–18186CrossRefPubMedGoogle Scholar
  57. Santa-Maria I, Hernandez F, Smith MA, Perry G, Avila J, Moreno FJ (2005) Neurotoxic dopamine quinone facilitates the assembly of tau into fibrillar polymers. Mol Cell Biochem 278:203–212CrossRefPubMedGoogle Scholar
  58. Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481CrossRefPubMedGoogle Scholar
  59. Schaffer BA, Bertram L, Miller BL, Mullin K, Weintraub S, Johnson N, Bigio EH, Mesulam M, Wiedau-Pazos M, Jackson GR, Cummings JL, Cantor RM, Levey AI, Tanzi RE, Geschwind DH (2008) Association of GSK3B with Alzheimer disease and frontotemporal dementia. Arch Neurol 65:1368–1374CrossRefPubMedGoogle Scholar
  60. Schneider A, Mandelkow E (2008) Tau-based treatment strategies in neurodegenerative diseases. Neurotherapeutics 5:443–457CrossRefPubMedGoogle Scholar
  61. Shelanski ML, Gaskin F, Cantor CR (1973) Microtubule assembly in the absence of added nucleotides. Proc Natl Acad Sci USA 70:765–768CrossRefPubMedGoogle Scholar
  62. Smith DG, Buffet M, Fenwick AE, Haigh D, Ife RJ, Saunders M, Slingsby BP, Stacey R, Ward RW (2001) 3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3). Bioorg Med Chem Lett 11:635–639CrossRefPubMedGoogle Scholar
  63. Sontag JM, Nunbhakdi-Craig V, Montgomery L, Arning E, Bottiglieri T, Sontag E (2008) Folate deficiency induces in vitro and mouse brain region-specific downregulation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A B(alpha) subunit expression that correlate with enhanced tau phosphorylation. J Neurosci 28:11477–11487CrossRefPubMedGoogle Scholar
  64. Steinhilb ML, Dias-Santagata D, Fulga TA, Felch DL, Feany MB (2007) Tau phosphorylation sites work in concert to promote neurotoxicity in vivo. Mol Biol Cell 18:5060–5068CrossRefPubMedGoogle Scholar
  65. Tortosa E, Santa-Maria I, Moreno F, Lim F, Perez M, Avila J (2009) Binding of Hsp90 to tau promotes a conformational change and aggregation of tau protein. J Alzheimers Dis 17:319–25Google Scholar
  66. Townsend M, Mehta T, Selkoe DJ (2007) Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem 282:33305–33312CrossRefPubMedGoogle Scholar
  67. Trinchese F, Fa M, Liu S, Zhang H, Hidalgo A, Schmidt SD, Yamaguchi H, Yoshii N, Mathews PM, Nixon RA, Arancio O (2008) Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease. J Clin Invest 118:2796–2807CrossRefPubMedGoogle Scholar
  68. Trojanowski JQ, Schuck T, Schmidt ML, Lee VM (1989) Distribution of tau proteins in the normal human central and peripheral nervous system. J Histochem Cytochem 37:209–215PubMedGoogle Scholar
  69. Tsujio I, Zaidi T, Xu J, Kotula L, Grundke-Iqbal I, Iqbal K (2005) Inhibitors of protein phosphatase-2A from human brain structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau. FEBS Lett 579:363–372CrossRefPubMedGoogle Scholar
  70. Wang JZ, Gong CX, Zaidi T, Grundke-Iqbal I, Iqbal K (1995) Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J Biol Chem 270:4854–4860CrossRefPubMedGoogle Scholar
  71. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 72:1858–1862CrossRefPubMedGoogle Scholar
  72. Wetzel MK, Naska S, Laliberte CL, Rymar VV, Fujitani M, Biernaskie JA, Cole CJ, Lerch JP, Spring S, Wang SH, Frankland PW, Henkelman RM, Josselyn SA, Sadikot AF, Miller FD, Kaplan DR (2008) p73 regulates neurodegeneration and phospho-tau accumulation during aging and Alzheimer’s disease. Neuron 59:708–721CrossRefPubMedGoogle Scholar
  73. Williamson R, Scales T, Clark BR, Gibb G, Reynolds CH, Kellie S, Bird IN, Varndell IM, Sheppard PW, Everall I, Anderton BH (2002) Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloid-beta peptide exposure: involvement of Src family protein kinases. J Neurosci 22:10–20PubMedGoogle Scholar
  74. Yoo BC, Lubec G (2001) p25 protein in neurodegeneration. Nature 411:763–764;discussion 764–765CrossRefPubMedGoogle Scholar
  75. Yu JY, Taylor J, DeRuiter SL, Vojtek AB, Turner DL (2003) Simultaneous inhibition of GSK3alpha and GSK3beta using hairpin siRNA expression vectors. Mol Ther 7:228–236CrossRefPubMedGoogle Scholar
  76. Yuan A, Kumar A, Peterhoff C, Duff K, Nixon RA (2008) Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice. J Neurosci 28:1682–1687CrossRefPubMedGoogle Scholar
  77. Yuzwa SA, Macauley MS, Heinonen JE, Shan X, Dennis RJ, He Y, Whitworth GE, Stubbs KA, McEachern EJ, Davies GJ, Vocadlo DJ (2008) A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol 4:483–490CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de MadridMadridSpain

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