Advertisement

Pathogenesis of the Tauopathies

  • Michel GoedertEmail author
  • Maria Grazia Spillantini
Article

Abstract

Microtubule-associated protein tau is the most commonly misfolded protein in human neurodegenerative diseases, where it becomes hyperphosphorylated and filamentous. Mutations in MAPT, the tau gene, cause approximately 5% of cases of frontotemporal dementia. They are frequently accompanied by parkinsonism. The existence of MAPT mutations has established that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. However, most tauopathies are not inherited in a dominant manner. The hyperphosphorylated sites are similar between diseases, but filament morphologies and tau isoform compositions vary. This is consistent with the existence of multiple tau conformers and recent findings have provided experimental support for this concept.

Keywords

Tau protein Tauopathies Alzheimer’s disease Pick’s disease Progressive supranuclear palsy Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T) 

References

  1. Alzheimer A (1907) Über eine eigenartige Erkrankung der Hirnrinde. Allg Z Psychiat 64:146–148Google Scholar
  2. Alzheimer A (1911) Über eigenartige Krankheitsfälle des späteren Alters. Z ges Neurol Psychiat 4:356–385CrossRefGoogle Scholar
  3. Andreadis A, Brown MW, Kosik KS (1992) Structure and novel exons of the human tau gene. Biochemistry 31:10626–10633PubMedCrossRefGoogle Scholar
  4. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M (2006) Mutations in progranulin cause tau-negative frontotempoal dementia linked to chromosome 17. Nature 442:916–919PubMedCrossRefGoogle Scholar
  5. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  6. Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121:171–181PubMedCrossRefGoogle Scholar
  7. Bramblett GT, Goedert M, Jakes R, Merrick SE, Trojanowski JQ, Lee VMY (1993) Abnormal tau phosphorylation at Ser396 in Alzheimer’s disease recapitulates development and contributes to reduced microtubule binding. Neuron 19:1089–1099CrossRefGoogle Scholar
  8. Brion JP, Passareiro H, Nunez J, Flament-Durand J (1985) Mise en évidence immunologique de la protéine tau au niveau des lésions de dégénérescence neurofibrillaire de la maladie d’Alzheimer. Arch Biol 95:229–235Google Scholar
  9. Bugiani O, Murrell JR, Giaccone G, Hasegawa M, Ghigo G, Tabaton M, Morbin M, Primavera A, Carella F, Solaro C, Grisoli M, Savoiardo M, Spillantini MG, Tagliavini F, Goedert M, Ghetti B (1999) Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol 58:667–677PubMedCrossRefGoogle Scholar
  10. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913PubMedCrossRefGoogle Scholar
  11. Colby DW, Prusiner SB (2011) Prions. Cold Spring Harb Perspect Biol 3:a006833PubMedCrossRefGoogle Scholar
  12. Crowther RA, Goedert M (2000) Abnormal tau-containing filaments in neurodegenerative diseases. J Struct Biol 130:271–279PubMedCrossRefGoogle Scholar
  13. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, van Broeckhoven C (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924PubMedCrossRefGoogle Scholar
  14. Delacourte A, Robitaille Y, Sergeant N, Buée L, Hof PR, Wattez A, Laroche-Cholette A, Mathieu J, Chagnon P, Gauvreau D (1996) Specific pathological tau protein variants characterize Pick’s disease. J Neuropathol Exp Neurol 55:159–168PubMedCrossRefGoogle Scholar
  15. Drewes G, Lichtenberg-Kraag B, Döring F, Mandelkow EM, Biernat J, Goris J, Dorée M, Mandelkow E (1992) Mitogen-activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J 11:2131–2138PubMedGoogle Scholar
  16. Drewes G, Ebneth A, Preuss U, Mandelkow EM, MandelkoW E (1997) MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89:298–308CrossRefGoogle Scholar
  17. Ennulat DJ, Liem RKH, Hashim GA, Shelanski ML (1989) Two separate 18-amino acid domains of tau promote the polymerization of tubulin. J Biol Chem 264:527–5330Google Scholar
  18. Fischer O (1907) Miliare Nekrosen mit drusigen Wucherungen der Neurofibrillen, eine regelmässige Veränderung der Hirnrinde bei seniler Demenz. Monatsschr Psychiat Neurol 22:361–372CrossRefGoogle Scholar
  19. Flament S, Delacourte A, Verny M, Hauw JJ, Javoy-Agid F (1991) Abnormal tau proteins in progressive supranuclear palsy. Similarities and differences with the neurofibrillary degeneration of the Alzheimer type. Acta Neuropathol 81:591–596PubMedCrossRefGoogle Scholar
  20. Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852PubMedCrossRefGoogle Scholar
  21. Ghetti B, Wszolek ZW, Boeve BF, Spina S, Goedert M (2011) Frontotemporal dementia and parkinsonism linked to chromosome 17. In: Dickson D, Weller RO (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edn. Blackwell, Oxford, pp 110–134CrossRefGoogle Scholar
  22. Goedert M (2009) Oskar Fischer and the study of dementia. Brain 132:1102–1111PubMedCrossRefGoogle Scholar
  23. Goedert M, Jakes R (1990) Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J 9:4225–4230PubMedGoogle Scholar
  24. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 85:4051–4055PubMedCrossRefGoogle Scholar
  25. Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA (1989a) Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: Differential expression of tau mRNAs in human brain. EMBO J 8:393–399PubMedGoogle Scholar
  26. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989b) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3:519–528PubMedCrossRefGoogle Scholar
  27. Goedert M, Spillantini MG, Cairns NJ, Crowther RA (1992a) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8:159–168PubMedCrossRefGoogle Scholar
  28. Goedert M, Cohen ES, Jakes R, Cohen P (1992b) p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase2A1. FEBS Lett 312:95–99PubMedCrossRefGoogle Scholar
  29. Goedert M, Jakes R, Spillantini MG, Hasegawa M, Smith MJ, Crowther RA (1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383:550–553PubMedCrossRefGoogle Scholar
  30. Goedert M, Jakes R, Crowther RA (1999) Effects of frontotemporal dementia FTDP-17 mutations on heparin-induced assembly of tau filaments. FEBS Lett 450:306–311PubMedCrossRefGoogle Scholar
  31. Goedert M, Klug A, Crowther RA (2006) Tau protein, the paired helical filament and Alzheimer’s disease. J Alz Dis 9:195–207Google Scholar
  32. Goedert M, Clavaguera F, Tolnay M (2010) The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci 33:317–325PubMedCrossRefGoogle Scholar
  33. Gozes I (2010) Tau pathology and future therapeutics. Curr Alz Res 7:685–696CrossRefGoogle Scholar
  34. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917PubMedCrossRefGoogle Scholar
  35. Hanger DP, Hughes K, Woodgett JR, Brion JP, Anderton BH (1992) Glycogen synthase kinase-3 induced Alzheimer’s disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localization of the kinase. Neurosci Lett 147:58–62PubMedCrossRefGoogle Scholar
  36. Hasegawa M, Smith MJ, Goedert M (1998) Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett 437:207–210PubMedCrossRefGoogle Scholar
  37. Höglinger GU, Melhem NM, Dickson DW, Sleiman PMA, Wang LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni B, Pastor P, PSP Genetics Study Group, Cantwell LB, Han MR, Dillman A, van der Burg MP, Gibbs JR, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu CE, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Müller U, Schellenberg GD (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699–705PubMedCrossRefGoogle Scholar
  38. Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BL, Geschwind DH, Bird TD, McKeel D, Goate A, Morris JC, Wilhelmsen KC, Schellenberg GD, Trojanowski JQ, Lee VMY (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282:1914–1917PubMedCrossRefGoogle Scholar
  39. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JBJ, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P (1998) Association of missense and 5′-splice site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705PubMedCrossRefGoogle Scholar
  40. Kampers T, Friedhoff P, Biernat J, Mandelkow EM, Mandelkow E (1996) RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett 399:344–349PubMedCrossRefGoogle Scholar
  41. Kertesz A, Martinez-Lage P, Davidson W, Munoz DG (2000) The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia. Neurology 55:1368–1375PubMedGoogle Scholar
  42. Kidd M (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197:192–193PubMedCrossRefGoogle Scholar
  43. Kobayashi S, Ishiguro K, Omori A, Takamatsu M, Arioka M, Imahori K, Uchida T (1993) A cdc-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubules. FEBS Lett 335:171–175PubMedCrossRefGoogle Scholar
  44. Komori T (1999) Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Brain Pathol 9:663–679PubMedCrossRefGoogle Scholar
  45. Koolen DA, Vissers LELM, Pfundt R, de Leuw N, Knight SJL, Regan R, Kooy RF, Reyniers E, Romano C, Fichera M, Schinzel A, Baumer A, Anderlid BM, Schoumans J, Knoers NV, Geurts van Kessel A, Sistermans EA, Veltman JA, Brunner HG, de Vries BBA (2006) A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet 38:999–1001PubMedCrossRefGoogle Scholar
  46. Ksiezak-Reding H, Morghan K, Mattiace LA, Davies P, Liu WK, Yen SH, Weidenheim K, Dickson DW (1994) Ultrastructure and biochemical composition of paired helical filaments in corticobasal degeneration. Am J Pathol 145:1496–1508PubMedGoogle Scholar
  47. Lee G, Neve RL, Kosik KS (1989) The microtubule-binding domain of tau protein. Neuron 2:1615–1624PubMedCrossRefGoogle Scholar
  48. Lee VMY, Balin LJ, Otvos L, Trojanowski JQ (1991) A68—a major subunit of paired helical filaments and derivatized forms of normal tau. Science 251:675–678PubMedCrossRefGoogle Scholar
  49. Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Titani K, Ihara Y (1993) Ubiquitin is conjugated with amino-terminally processed tau in paired helical filamens. Neuron 10:1151–1160PubMedCrossRefGoogle Scholar
  50. Morris M, Maeda S, Vossel K, Mucke L (2011) The many faces of tau. Neuron 70:410–426PubMedCrossRefGoogle Scholar
  51. Myers AJ, Pittman AM, Zhao AS, Rohrer K, Kaleem M, Marlowe L, Lees A, Leung D, McKeith IG, Perry RH, Morris CM, Trojanowski JQ, Clark C, Karlawish J, Arnold S, Forman MS, van Deerlin V, de Silva R, Hardy J (2007) The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol Dis 25:561–570PubMedCrossRefGoogle Scholar
  52. Nacharaju P, Lewis J, Easson C, Yen S, Hackett J, Hutton M, Yen SH (1999) Accelerated filament formation from tau protein with specific FTDP-17 mutations. FEBS Lett 447:195–199PubMedCrossRefGoogle Scholar
  53. Pastor P, Ezquerra M, Munoz E, Marti MJ, Blesa R, Tolosa E, Oliva R (2000) Significant association between the tau gene A0/A0 genotype and Parkinson’s disease. Ann Neurol 47:242–245PubMedCrossRefGoogle Scholar
  54. Pérez M, Valpuesta JM, Medina M, Montejo de Garcini E, Avila J (1996) Polymerization of tau into filaments in the presence of heparin: the minimal sequence required for tau–tau interaction. J Neurochem 67:1183–1190PubMedCrossRefGoogle Scholar
  55. Pittman AM, Myers AJ, Abou-Sleiman P, Fung HC, Kaleem M, Marlowe L, Duckworth J, Leung D, Williams D, Kilford L, Thomas N, Morris CM, Dickson D, Wood NW, Hardy J, Lees AJ, de Silva R (2005) Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J Med Genet 42:837–846PubMedCrossRefGoogle Scholar
  56. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815–825PubMedCrossRefGoogle Scholar
  57. Rademakers R, Melquist S, Cruts M, Theuns J, Del-Favero J, Poorkaj P, Baker M, Sleegers K, Crook R, De Pooter T, Bel Kacem S, Adamson J, van den Bossche D, van den Broeck M, Gass J, Corsmit E, De Rijk P, Thomas N, Engelborghs S, Heckman M, Litvan I, Crook J, De Deyn PP, Dickson D, Schellenberg GD, van Broeckhoven C, Hutton ML (2005) High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet 14:3281–3292PubMedCrossRefGoogle Scholar
  58. Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA, Stewart H, Price SM, Blair E, Hennekam RC, Fitzpatrick CA, Segraves R, Richmond TA, Guiver C, Albertson DG, Pinkel D, Eis PS, Schwartz S, Knight SJL, Eichler EE (2006) Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 68:812–814Google Scholar
  59. Shaw-Smith C, Pittman AM, Willatt L, Martin H, Rickman L, Gribble S, Curley R, Cumming S, Dunn C, Kalaitzopoulos D, Porter K, Prigmore E, Krepischi-Santos ACV, Varela MC, Koiffmann CP, Lees AJ, Rosenberg C, Firth HV, de Silva R, Carter NP (2006) Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet 38:1032–1037PubMedCrossRefGoogle Scholar
  60. Simón-Sánchez J, Schultew C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Krüger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41:1308–1312PubMedCrossRefGoogle Scholar
  61. Spillantini MG, Goedert M, Crowther RA, Murrell JR, Farlow MR, Ghetti B (1997) Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci USA 94:4113–4118PubMedCrossRefGoogle Scholar
  62. Spillantini MG, Bird TD, Ghetti B (1998a) Frontotemporal dementia and parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol 8:387–402PubMedCrossRefGoogle Scholar
  63. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B (1998b) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 95:7737–7741PubMedCrossRefGoogle Scholar
  64. Stefansson H, Helgason A, Thorleifsson G, Steintorsdottir V, Masson G, Barnard J, Baker A, Jonasdottir A, Ingason A, Gudnadottir VG, Desnica N, Hicks A, Gylfason A, Gudbjartsson DF, Jonsdottir GM, Sainz J, Agnarsson K, Birgisdottir B, Ghosh S, Olafsdottir A, Cazier JB, Kristjansson K, Frigge ML, Thorgeirsson TE, Gulcher JR, Kong A, Stefansson K (2005) A common inversion under selection in Europeans. Nat Genet 37:129–137PubMedCrossRefGoogle Scholar
  65. Vandrovcova J, Pittman AM, Malzer E, Abou-Sleiman PM, Lees AJ, Wood NW, de Silva R (2009) Association of MAPT haplotype-tagging SNPs with sporadic Parkinson’s disease. Neurobiol Aging 30:1477–1482PubMedCrossRefGoogle Scholar
  66. Wilhelmsen KC, Lynch T, Pavlou E, Higgins M, Nygaard TG (1994) Localization of disinhibition-dementia-parkinsonism-amyotrophy complex to 17q21-22. Am J Hum Genet 55:1159–1165PubMedGoogle Scholar
  67. Williams DR, Lees AJ (2009) Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 8:270–279PubMedCrossRefGoogle Scholar
  68. Wischik CM, Novak M, Thogersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, Milstein C, Roth M, Klug A (1988) Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 85:4506–4510PubMedCrossRefGoogle Scholar
  69. Yoshida H, Ihara Y (1993) Tau in paired helical filament is functionally distinct from fetal tau: assembly incompetence of paired helical filament tau. J Neurochem 61:1183–1186PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.MRC Laboratory of Molecular BiologyCambridgeUK
  2. 2.Centre for Brain Repair, Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK

Personalised recommendations