SpringerLink
Log in

The novel Tau mutation G335S: clinical, neuropathological and molecular characterization

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Mutations in Tau cause the inherited neurodegenerative disease, frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Known coding region mutations cluster in the microtubule-binding region, where they alter the ability of tau to promote microtubule assembly. Depending on the tau isoforms, this region consists of three or four imperfect repeats of 31 or 32 amino acids, each of which contains a characteristic and invariant PGGG motif. Here, we report the novel G335S mutation, which changes the PGGG motif of the third tau repeat to PGGS, in an individual who developed social withdrawal, emotional bluntness and stereotypic behavior at age 22, followed by disinhibition, hyperorality and ideomotor apraxia. Abundant tau-positive inclusions were present in neurons and glia in the frontotemporal cortex, hippocampus and brainstem. Sarkosyl-insoluble tau showed paired helical and straight filaments, as well as more irregular rope-like filaments. The pattern of pathological tau bands was like that of Alzheimer disease. Experimentally, the G335S mutation resulted in a greatly reduced ability of tau to promote microtubule assembly, while having no significant effect on heparin-induced assembly of recombinant tau into filaments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. 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 frontotemporal dementia linked to chromosome 17. Nature 442:916–919

    Article  PubMed  CAS  Google Scholar 

  2. Boeve BF, Tremont-Lukats IW, Waclawik AJ, Murrell JR, Hermann B, Jack CR Jr, Shiung MM, Smith GE, Nair AR, Lindor N, Koppikar V, Ghetti B (2005) Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N mutation. Brain 128:752–772

    Article  PubMed  Google Scholar 

  3. 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 58:667–677

    PubMed  CAS  Google Scholar 

  4. 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 442:920–924

    Article  PubMed  CAS  Google Scholar 

  5. Delobel P, Flament S, Hamdane M, Jakes R, Rousseau A, Delacourte A, Vilain JP, Goedert M, Buee L (2002) Functional characterization of FTDP-17 tau gene mutations through their effects on Xenopus oocyte maturation. J Biol Chem 277:9199–9205

    Article  PubMed  CAS  Google Scholar 

  6. Donahue CP, Muratore C, Wu JY, Kosik KS, Wolfe MS (2006) Stabilization of tau exon 10 stem loop alters pre-mRNA splicing. J Biol Chem 281:23302–23306

    Article  PubMed  CAS  Google Scholar 

  7. Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, Crook R, Melquist S, Kuntz K, Petersen R, Josephs K, Pickering-Brown SM, Graff-Radford N, Uitti R, Dickson D, Wszolek Z, Gonzales J, Beach TG, Bigio E, Johnson N, Weintraub S, Mesulam M, White III CL, Woodruff B, Caselli R, Hsiung G, Feldman H, Knopman D, Hutton M, Rademakers R (2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15:2988–3001

    Article  PubMed  CAS  Google Scholar 

  8. 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 9:4225–4230

    PubMed  CAS  Google Scholar 

  9. Goedert M, Spillantini MG, Cairns NJ, Crowther RA (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8:159–168

    Article  PubMed  CAS  Google Scholar 

  10. 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 383:550–553

    Article  PubMed  CAS  Google Scholar 

  11. Goedert M, Jakes R, Crowther RA (1999) Effects of frontotemporal dementia FTDP-17 mutations on heparin-induced assembly of tau filaments. FEBS Lett 450:306–311

    Article  PubMed  CAS  Google Scholar 

  12. Goedert M, Jakes R (2005) Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta 1739:240–250

    PubMed  CAS  Google Scholar 

  13. Hasegawa M, Smith MJ, Goedert M (1998) Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett 437:207–210

    Article  PubMed  CAS  Google Scholar 

  14. Hasegawa M, Smith MJ, Goedert M (1999) FTDP-17 mutations N279K and S305N in tau produce increased splicing of exon 10. FEBS Lett 443:93–96

    Article  PubMed  CAS  Google Scholar 

  15. Hayashi S, Toyoshima Y, Hasegawa M, Umeda Y, Wakabayashi K, Tokiguchi S, Iwatsubo T, Takahashi H (2002) Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Ann Neurol 51:525–530

    Article  PubMed  CAS  Google Scholar 

  16. 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 JB, 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 393:702–705

    Article  PubMed  CAS  Google Scholar 

  17. Iijima M, Tabira T, Poorkaj P, Schellenberg GD, Trojanowski JQ, Lee VM, Schmidt ML, Takahashi K, Nabika T, Matsumoto T, Yamashita Y, Yoshioka S, Ishino H (1999) A distinct familial presenile dementia with a novel missense mutation in the tau gene. Neuroreport 10:497–501

    Article  PubMed  CAS  Google Scholar 

  18. Kobayashi T, Ota S, Tanaka K, Ito Y, Hasegawa M, Umeda Y, Motoi Y, Takanashi M, Yasuhara M, Anno M, Mizuno Y, Mori H (2003) A novel L266V mutation of the tau gene causes frontotemporal dementia with unique tau pathology. Ann Neurol 53:133–137

    Article  PubMed  CAS  Google Scholar 

  19. Lee VMY, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159

    Article  PubMed  CAS  Google Scholar 

  20. Lynch T, Sano M, Marder KS, Bell KL, Foster NL, Defendini RF, Sima AA, Keohane C, Nygaard TG, Fahn S, Mayeux R, Rowland LP, Wilhelmsen KC (1994) Clinical characteristics of a family with chromosome 17-linked disinhibition–dementia–parkinsonism–amyotrophy complex. Neurology 44:1878–1884

    PubMed  CAS  Google Scholar 

  21. Murrell J, Farlow M, Ghetti B, Benson MD (1991) A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science 254:97–99

    Article  PubMed  CAS  Google Scholar 

  22. Murrell JR, Spillantini MG, Zolo P, Guazzelli M, Smith MJ, Hasegawa M, Redi F, Crowther RA, Pietrini P, Ghetti B, Goedert M (1999) Tau gene mutation G389R causes a tauopathy with abundant Pick body-like inclusions and axonal deposits. J Neuropathol Exp Neurol 58:1207–1226

    PubMed  CAS  Google Scholar 

  23. 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 missense mutations. FEBS Lett 447:195–199

    Article  PubMed  CAS  Google Scholar 

  24. Neary D, Snowden J, Mann D (2005) Frontotemporal dementia. Lancet Neurol 4:771–780

    Article  PubMed  Google Scholar 

  25. Neumann M, Diekmann S, Bertsch U, Vanmassenhove B, Bogerts B, Kretzschmar HA (2005) Novel G335V mutation in the tau gene associated with early onset familial frontotemporal dementia. Neurogenetics 6:91–95

    Article  PubMed  Google Scholar 

  26. Nicholl DJ, Greenstone MA, Clarke CE, Rizzu P, Crooks D, Crowe A, Trojanowski JQ, Lee VM, Heutink P (2003) An English kindred with a novel recessive tauopathy and respiratory failure. Ann Neurol 54:682–686

    Article  PubMed  CAS  Google Scholar 

  27. Pickering-Brown SM, Baker M, Nonaka T, Ikeda K, Sharma S, Mackenzie J, Simpson SA, Moore JW, Snowden JS, de Silva R, Revesz T, Hasegawa M, Hutton M, Mann DM (2004) Frontotemporal dementia with Pick-type histology associated with Q336R mutation in the tau gene. Brain 127:1415–1426

    Article  PubMed  CAS  Google Scholar 

  28. 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 43:815–825

    Article  PubMed  CAS  Google Scholar 

  29. Poorkaj P, Muma NA, Zhukareva V, Cochran EJ, Shannon KM, Hurtig H, Koller WC, Bird TD, Trojanowski JQ, Lee VM, Schellenberg GD (2002) An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype. Ann Neurol 52:511–516

    Article  PubMed  Google Scholar 

  30. Ratnavalli E, Brayne C, Dawson K, Hodges JR (2002) The prevalence of frontotemporal dementia. Neurology 58:1615–1621

    PubMed  CAS  Google Scholar 

  31. Ros R, Thobois S, Streichenberger N, Kopp N, Sanchez MP, Perez M, Hoenicka J, Avila J, Honnorat J, de Yebenes JG (2005) A new mutation of the tau gene, G303V, in early-onset familial progressive supranuclear palsy. Arch Neurol 62:1444–1450

    Article  PubMed  Google Scholar 

  32. Skibinski G, Parkinson NJ, Brown JM, Chakrabarti L, Lloyd SL, Hummerich H, Nielsen JE, Hodges JR, Spillantini MG, Thusgaard T, Brandner S, Brun A, Rossor MN, Gade A, Johannsen P, Sorensen SA, Gydesen S, Fisher EM, Collinge J (2005) Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet 37:806–808

    Article  PubMed  CAS  Google Scholar 

  33. Spillantini MG, Crowther RA, Goedert M (1996) Comparison of the neurofibrillary pathology in Alzheimer’s disease and familial presenile dementia with tangles. Acta Neuropathol 92:42–48

    Article  PubMed  CAS  Google Scholar 

  34. 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 94:4113–4118

    Article  PubMed  CAS  Google Scholar 

  35. Spillantini MG, Crowther RA, Kamphorst W, Heutink P, van Swieten JC (1998) Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. Am J Pathol 153:1359–1363

    PubMed  CAS  Google Scholar 

  36. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 95:7737–7741

    Article  PubMed  CAS  Google Scholar 

  37. Takao M, Ghetti B, Yoshida H, Piccardo P, Narain Y, Murrell JR, Vidal R, Glazier BS, Jakes R, Tsutsui M, Spillantini MG, Crowther RA, Goedert M, Koto A (2004) Early onset dementia with Lewy bodies. Brain Pathol 14:137–147

    Article  PubMed  Google Scholar 

  38. van der Zee J, Rademakers R, Engelborghs S, Gijselinck I, Bogaerts V, Vandenberghe R, Santens P, Caekebeke J, De Pooter T, Peeters K, Lubke U, Van den Broeck M, Martin JJ, Cruts M, De Deyn PP, Van Broeckhoven C, Dermaut B (2006) A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. Brain 129:841–852

    Article  PubMed  Google Scholar 

  39. van Herpen E, Rosso SM, Serverijnen LA, Yoshida H, Breedveld G, van de Graaf R, Kamphorst W, Ravid R, Willemsen R, Dooijes D, Majoor-Krakauer D, Kros JM, Crowther RA, Goedert M, Heutink P, van Swieten JC (2003) Variable phenotypic expression and extensive tau pathology in two families with the novel tau mutation L315R. Ann Neurol 54:573–581

    Article  PubMed  CAS  Google Scholar 

  40. Varani L, Hasegawa M, Spillantini MG, Smith MJ, Murrell JR, Ghetti B, Klug A, Goedert M, Varani G (1999) Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17. Proc Natl Acad Sci USA 96:8229–8234

    Article  PubMed  CAS  Google Scholar 

  41. Watts GDJ, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36:377–381

    Article  PubMed  CAS  Google Scholar 

  42. Wechsler D (1981) WAIS-R manual. The Psychological Corporation, New York

  43. Wechsler D (1987) Wechsler memory scale-revised manual. The Psychological Corporation, San Antonio

  44. Yoshida H, Crowther RA, Goedert M (2002) Functional effects of tau gene mutations deltaN296 and N296H. J Neurochem 80:548–551

    Article  PubMed  CAS  Google Scholar 

  45. Yoshida H, Goedert M (2002) Molecular cloning and functional characterization of chicken brain tau: isoforms with up to five tandem repeats. Biochemistry 41:15203–15211

    Article  PubMed  CAS  Google Scholar 

  46. Yoshida H, Goedert M (2006) Sequential phosphorylation of tau protein by cAMP-dependent protein kinase and SAPK4/p38Δ or JNK2 in the presence of heparin generates the AT100 epitope. J Neurochem 99:154–164

    Article  PubMed  CAS  Google Scholar 

  47. Zarranz JJ, Ferrer I, Lezcano E, Forcadas MI, Eizaguirre B, Atares B, Puig B, Gomez-Esteban JC, Fernandez-Maiztegui C, Rouco I, Perez-Concha T, Fernandez M, Rodriguez O, Rodriguez-Martinez AB, de Pancorbo MM, Pastor P, Perez-Tur J (2005) A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease. Neurology 64:1578–1585

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Institute on Aging P30 AG10133, the UK Medical Research Council and the UK Alzheimer’s Research Trust. S.S. is in part supported by and is a Ph.D. student of the Department of Neurological and Behavioral Sciences, University of Siena, Siena, Italy. The authors are grateful to Brenda Dupree, Brad Glazier, Urs Kuederli, and, particularly, Rose Richardson for their technical assistance.

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive MS A138, Indianapolis, IN, 46202, USA

    Salvatore Spina, Jill R. Murrell & Bernardino Ghetti

  2. Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

    Hirotaka Yoshida, R. Anthony Crowther & Michel Goedert

  3. Neuroscience Division, Cork University Hospital, Wilton, Cork, Ireland

    Niamh Bermingham, Brian Sweeney & Catherine Keohane

  4. Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 West Walnut Street, Medical Research and Library Building, Indianapolis, IN, IB 130, USA

    Stephen R. Dlouhy

Authors
  1. Salvatore Spina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jill R. Murrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hirotaka Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bernardino Ghetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Niamh Bermingham
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Brian Sweeney
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stephen R. Dlouhy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. Anthony Crowther
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michel Goedert
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Catherine Keohane
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernardino Ghetti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spina, S., Murrell, J.R., Yoshida, H. et al. The novel Tau mutation G335S: clinical, neuropathological and molecular characterization. Acta Neuropathol 113, 461–470 (2007). https://doi.org/10.1007/s00401-006-0182-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-006-0182-5

Keywords

Search

Navigation