by Jennifer Kwon, MD., Washington University, St. Louis, with updates by Michael Hutton and Eckhard Mandelkow

View Tau Mutation Table
View Tau Polymorphism Table
Axonal Transport Dysfunction Hypothesis

Introduction
Tau is a microtubule-associated protein that is involved in microtubule assembly and stabilization. In adult human brain, six tau isoforms are produced from a single gene by alternative mRNA splicing. They differ from each other by the presence or absence of 29- or 58- amino-acid inserts located in the amino-terminal half and 31-amino acid repeat located in the carboxy-terminal half. Inclusion of the latter, which is encoded by exon 10 of the tau gene, gives rise to the three tau isoforms which each have 4 repeats. In the normal cerebral cortex, there is a slight preponderance of 3 repeat over 4 repeat tau isoforms. These repeats and some adjoining sequences consititute the microtubule-binding domain of tau (Goedert, et al., 1998).

One of the pathologic hallmarks of Alzheimer's disease (AD) are neurofibrillary tangles, intraneuronal deposits of paired helical filaments (and fewer straight filaments) made of hyperphosphorylated tau. Abnormal deposition of tau is also seen in a variety of other neurodegenerative disorders including progressive supranuclear palsy (PSP), corticobasal ganglionic degeneration (CBD), and frontotemporal dementias. Variability in the tau gene has been shown to be a risk factor for PSP (Conrad, et al.). Recent studies have shown that mutations in the coding and non-coding regions of tau are directly associated with the development of familial frontotemporal dementia (FTD).

Forms of FTD have been variously referred to in the literature as disinhibition- dementia- parkinsonism- amyotrophy complex (DDPAC), hereditary frontotemporal dementia (HFTD), multiple system tauopathy dementia (MSTD), and pallidopontonigral dementia (PPND), the syndrome name depending in part on particular prominent clinical and/or pathologic findings. The various forms of FTD generally share in common insidious onset of behavior or personality change and dementia typically in the fifth decade, with other motor findings (Foster, et al.). Duration is quite variable. The prominent clinical findings in those affected include: impaired social conduct, diminished speech progressing to muteness, progressive dementia notable for disturbed executive function and parkinsonian extrapyramidal disorders.

Pathologically, frontotemporal atrophy is a consistent finding which may be accompanied by basal ganglia atrophy and substantia nigra depigmentation. Many families have tau positive inclusions either in neurons or in neurons and glia. And where linkage data was available, familial forms of FTD were linked to chromosome 17. A consensus conference decided that the term FTD with parkinsonism linked to chromosome 17 (FTDP-17) was preferred as it stressed the common clinical and pathologic features shared by this autosomal dominant, neurodegenerative condition (Foster, et al.).

In 1998, a series of papers reported that mutations in tau were associated with FTDP-17 (Hutton, et al.; Poorkaj, et al.; Spillantini, et al., 1997). Since then, other mutations have been described and are outlined in the accompanying table. The mutations causing various forms of FTD are of two major types (Goedert, et al., 1998), coding mutations and intronic mutations. Most coding mutations occur in the microtubule binding repeat region or very close to it. These potentially lead to a partial loss of function of tau with reduced tau binding to microtubules (Hong, et al.; Dayanandan, et al.; Hasegawa, et al., 1998; Goedert, et al., 1998; Spillantini and Goedert). There is also convincing evidence that tau missense mutations directly increase the tendency of tau to aggregate into filaments (Nacharaju, et al., and Goedert, et al.). Some missense mutations (G272V in exon 9, V337M in exon 12 and R406W in exon 13) affect all isoforms produced, while P301L only alters those isoforms with 4 repeats. The intronic mutations are all near the splice donor site of the intron following exon 10. By presumably destabilizing a predicted RNA stem-loop, there is a change in the ratio of 3-repeat to 4-repeat isoforms (Hutton, et al.; Spillantini, Murrell, et al.). There are two coding mutations, N279K and S305N which appear to enhance splicing of exon 10 rather than to reduce microtubule assembly (D'Souza, et al.; Hasegawa, et al., 1999). Yet it remains unclear how an increase in tau 4-repeat isoforms leads to frontotemporal dementia. Conversely, the delK280 mutation reduces splicing (D'Souza, et al.). Again, the significance of this reduction is unclear.

Although the various mutations in tau are associated with frontotemporal dementia, there are distinctive clinical and pathologic features which seem to be found with particular mutations. These are briefly summarized in the Tau Mutations Table. It is clear that the variable tau isoform content in FTDP-17 tangles is largely explained by the nature of the mutations: Mutations in or near exon 10 result in tangles consisting predominantly of 4-repeat tau, while mutations outside exon 10 are associated with tangles with both 4-repeat and 3-repeat tau. These latter tangles seem to result in filament morphology that is very similar to that seen in Alzheimer's disease. The filament morphology of 4-repeat tangles is more variable but generally they have a longer periodicity than the PHFs seen in AD. Mutations in exon 10 do give glial inclusions and those outside exon 10 generally do not (but there is at least one exception in press).

Improvements in assays of the functional effects of the tau mutations may enable us to link the size of these effects to the severity of the clinical phenotype. It already seems likely that a large effect on micortubule-binding and tau aggregation equates to a more severe phenotype. In addition, the exon 10 splice site mutations appear to correlate with clinical phenotype based on the degree to which they disrupt splicing (thus the +16 mutation appears to be the mildest with incomplete penetrance while the +3 and +14 are most severe).

We would like to thank Michael Hutton for his advice in the preparation of this page.

Additional Reading

Benoit I. Giasson, Christina A. Wilson, John Q. Trojanowski, and Virginia M.-Y Lee. Tau and Alpha-Synuclein Dysfunction and Aberrant Aggregates Define Distinct Neurodegenerative Diseases. No abstract available.

Hardy J, Pittman A, Myers A, Gwinn-Hardy K, Fung HC, de Silva R, Hutton M, Duckworth J. Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens. Biochem Soc Trans. 2005 Aug 1 ; 33(Pt 4):582-5. Abstract

Luc Buee, Thierry Bussiere, Valerie Buee-Scherrer, Andre Delacourte, Patrick R. Hof. Tau protein isoforms, phosphorylation and Role in Neurodegenerative Disease. Brain Research Review. Abstract.

References

Arawaka S, Usami M, Sahara N, Schellenberg GD, Lee G, Mori H (1999) The tau mutation (val337met) disrupts cytoskeletal networks of microtubules. Neuroreport 10: 993-997. Abstract.

Baker M, Kwok JBJ, Kucera S, Crook R, Farrer M, Houlden H, Isaacs A, Lincoln S, Onstead L, Hardy J, Wittenberg L, Dodd P, Webb S, Hayward N, Tannenberg T, Andreadis A, Hallupp M, Schofield P, Dark F, Hutton M (1997) Localization of Frontotemporal Dementia With Parkinsonism in an Australian Kindred to Chromosome 17q21-22. Annals of Neurology 42: 794-798. Abstract.

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. Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol 1999. Jun;58(6):667-77. Abstract.

Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, Li D, Payami H, Awert F, Markopoulou K, Andreadis A, D'Souza I, Lee VMY, Reed L, Trojanowski JQ, Zhukareva V, Bird T, Schellenberg G, Wilhelmsen KC (1998). Pathogenic Implications of Mutations in the Tau Gene in Pallido-Ponto-Nigral Degeneration and Related Neurodegenerative Disorders Linked to Chromosome 17. Proc Natl Acad Sci 95: 13103-13107. Abstract.

Conrad C, Andreadis A, Trojanowski JQ, Dickson DW, Kang D, Chen XH, Wiederholt W, Hansen L, Masliah E, Thal LJ, Katzman R, Xia Y, Saitoh T (1997) Genetic Evidence For the Involvement Of Tau In Progressive Supranuclear Palsy. Annals of Neurology 41: 277-281. Abstract.

D'Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM-Y, Bird TD, Schellenberg GD (1999) Missense and silent tau gene mutations cause frontotemporal dementia and parkinsonism- chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. PNAS 96: 5598-5603. Abstract.

Dayanandan R, Van Slegtenhorst M, Mack TGA, Ko L, Yen SH, Leroy K, Brion JP, Anderton BH, Hutton M, Lovestone S (1999) Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation. FEBS Letters 446: 228-232. Abstract.

Foster NL, Wilhelmsen K, Sima AAF, Jones MZ, Damato CJ, Gilman S, Spillantini MG, Lynch T, Mayeux RP, Gaskell PC, Hulette CM, Pericakvance MA, Welshbohmer KA, Dickson DW, Heutink P, Kros J, Vanswieten JC, Arwert F, Ghetti MB, Murrell J, Lannfelt L, Hutton M, Jones M, Phelps CH, Snyder DS, et al. (1997) Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 - a Consensus Conference. Annals of Neurology 41: 706-715. Abstract.

Goedert M. Tau gene mutations and their effects. Mov Disord. 2005 Aug 9;20(S12):S45-S52. Abstract.

Goedert M, Crowther RA, Spillantini MG (1998) Tau mutations cause frontotemporal dementias [Review]. Neuron 21: 955-958. No abstract available.

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

Goedert M, Spillantini MG, Crowther RA, Chen SG, Parchi P, Tabaton M, Lanska DJ, Markesbery WR, Wilhelmsen KC, Dickson DW, Petersen RB, Gambetti P (1999b) Tau gene mutation in familial progressive subcortical gliosis. Nature Medicine 5: 454-457. Abstract.

Hasegawa M, Smith MJ, Goedert M (1998) Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett. 1998 Oct 23;437(3):207-10. Abstract.

Hasegawa M, Smith MJ, Iijima M, Tabira T, Goedert M (1999) FTDP-17 mutations N279K and S305N in tau produce increased splicing of exon 10. FEBS Letters 443: 93-96. Abstract.

Heutink P, Stevens M, Rizzu P, Bakker E, Kros JM, Tibben A, Niermeijer MF, Vanduijn CM, Oostra BA, Vanswieten JC (1997) Hereditary frontotemporal dementia is linked to chromosome 17q21-q22: a genetic and clinicopathological study of three Dutch families. Ann Neurol. 1997 Feb;41(2):150-9. Abstract.

Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, 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: 1914-1917. Abstract.

Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickeringbrown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, Degraaff E, Wauters E, Vanbaren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, et al. (1998) Association Of Missense and 5'-Splice-Site Mutations In Tau With the Inherited Dementia Ftdp-17. Nature 393: 702-705. Abstract.

Iijima M, Tabira T, Poorkaj P, Schellenberg GD, Trojanowski JQ, Lee VMY, 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. Abstract.

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

Mirra SS, Murrell JR, Gearing M, Spillantini MG, Goedert M, Crowther A, Levey AI, Jones R, Green J, Shoffner JM, Wainer BH, Schmidt ML, Trojanowski JQ, Ghetti B (1999) Tau pathology in a family with dementia and a P301L mutation in tau. Journal of Neuropathology & Experimental Neurology 58: 335-345. Abstract.

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 Letters 447: 195-199. Abstract.

Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration - A consensus on clinical diagnostic criteria. Neurology 51: 1546-1554. Abstract.

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. 1998 Jun;43(6):815-25. Abstract.

Reed LA, Grabowski TJ, Schmidt ML, Morris JC, Goate A, Solodkin A, Vanhoesen GW, Schelper RL, Talbot CJ, Wragg MA, Trojanowski JQ (1997) Autosomal dominant dementia with widespread neurofibrillary tangles. Ann Neurol. 1997 Oct;42(4):564-72. Abstract.

Reed LA, Schmidt ML, Wszolek ZK, Balin BJ, Soontornniyomkij V, Lee VMY, Trojanowski JQ, Schelper RL (1998) The Neuropathology Of a Chromosome 17-Linked Autosomal Dominant Parkinsonism and Dementia (Pallido-Ponto-Nigral Degeneration). Journal of Neuropathology & Experimental Neurology 57: 588-601. Abstract.

Rizzu P, Van Swieten JC, Joosse M, Hasegawa M, Stevens M, Tibben A, Niermeijer MF, Hillebrand M, Ravid R, Oostra BA, Goedert M, van Duijn CM, Heutink P (1999) High Prevalence of Mutations in the Microtubule-Associated Protein Tau in a Population Study of Frontotemporal Dementia in the Netherlands. Am J Hum Genet 64: 414-421. Abstract.

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. Abstract.

Spillantini MG, Crowther RA, Kamphorst W, Heutink P, Vanswieten JC (1998) Tau Pathology In Two Dutch Families With Mutations In the Microtubule-Binding Region Of Tau. American Journal of Pathology 153: 1359-1363. Abstract.

Spillantini MG, Goedert M (1998) Tau protein pathology in neurodegenerative diseases [Review]. Trends in Neurosciences 21: 428-433. Abstract.

Spillantini MG, Goedert M, Crowther RA, Murrell JR, Farlow MR, Ghetti BFamilial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4113-8. Abstract.

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. Proceedings of the National Academy of Sciences of the United States of America 95: 7737-7741. Abstract.

Sumi SM, Bird TD, Nochlin D, Raskind MA. Familial presenile dementia with psychosis associated with cortical neurofibrillary tangles and degeneration of the amygdala. Neurology. 1992 Jan;42(1):120-7. Abstract.

More Recent References

Alonso AD, Zaidi T, Novak M, Barra HS, Grundke-Iqbal I, Iqbal K. Tau isoforms: Interaction with Alzheimer disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein. J Biol Chem. 2001 Aug 8 Abstract

Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6923-8. Abstract.

Bird TD, Nochlin D, Poorkaj P, Cherrier M, Kaye J, Payami H, Peskind E, Lampe TH, Nemens E, Boyer PJ, Schellenberg GD. A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene. Brain1999 Apr;122 ( Pt 4):741-56. Published erratum appears in Brain 1999. Jul;122(Pt 7):1398. Abstract.

Frappier T, Liang NS, Brown K, Leung CL, Lynch T, Liem RK, Shelanski ML. Abnormal microtubule packing in processes of SF9 cells expressing the FTDP-17 V337M tau mutation. FEBS Lett 1999 Jul 23;455(3):262-6. Abstract.

Grover A, Houlden H, Baker M, Adamson J, Lewis J, Prihar G, Pickering-Brown S, Duff K, Hutton M. 5' splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10. J Biol Chem 1999 May 21;274(21):15134-43 . Abstract.

Nasreddine ZS, Loginov M, Clark LN, Lamarche J, Miller BL, Lamontagne A, Zhukareva V, Lee VM, Wilhelmsen KC, Geschwind DH. From genotype to phenotype: a clinical pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation. Ann Neurol 1999 Jun;45(6):704-15. Abstract.

Pickering-Brown SM, Baker M, Yen SH, Liu WK, Hasegawa M, Cairns N, Lantos PL, Rossor M, Iwatsubo T, Davies Y, Allsop D, Furlong R, Owen F, Hardy J, Mann D, Hutton M. Pick's disease is associated with mutations in the tau gene. Ann Neurol. 2000 48(6):859-67. Abstract

Varani L, Hasegawa M, Spillantini MG, Smith MJ, Murrell JR, Ghetti B, Klug A, Goedert M, Varani G. 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 U S A 1999 Jul 6;96(14):8229-34. Abstract.

Yasuda M, Takamatsu J, D'Souza I, Crowther RA, Kawamata T, Hasegawa M, Hasegawa H, Spillantini MG, Tanimukai S, Poorkaj P, Varani L, Varani G, Iwatsubo T, Goedert M, Schellenberg DG, Tanaka C. A novel mutation at position +12 in the intron following exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto). Ann Neurol. 2000 Apr;47(4):422-9. Absrtact.

Yen SH, Hutton M, DeTure M, Ko LW, Nacharaju P. Fibrillogenesis of tau: insights from tau missense mutations in FTDP-17. Brain Pathol 1999. Oct;9(4):695-705. Abstract.