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Frontotemporal dementia and tauopathy

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Abstract

The presence of abundant neurofibrillary lesions made of hyperphosphorylated tau proteins is the characteristic neuropathology of a subset of neurodegenerative disorders classified as “tauopathies.” The discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. Moreover, it now is known that the most common form of sporadic frontotemporal dementia (FTD), which is characterized by frontotemporal neuron loss, gliosis, and microvacuolar change, also is a tauopathy caused by a loss of tau protein expression. Thus, these discoveries have begun to change the classification and the neuropathologic diagnosis of FTD and tauopathies, as well as current understanding of the disease mechanisms underlying them. Although transgenic mice expressing wild-type human tau or variants thereof with an FTDP-17 mutation result in tau pathologies and brain degeneration similar to that seen in human tauopathies, the precise mechanisms leading to the onset and progression of neurodegenerative disorders remain incompletely understood. Here, we review current understanding of human neurodegenerative tauopathies and prospects for translative recent insights about these into therapeutic interventions to prevent or ameliorate them.

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References and Recommended Reading

  1. Rizzu P, Van Swieten JC, Joosse M, et al.: High prevalence of mutations in the MT-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet 1999, 64:414–421.

    Article  PubMed  CAS  Google Scholar 

  2. Sjogren M, Rosengren L, Minthon L, et al.: Cytoskeleton proteins in CSF destinguish frontotemporal dementia from AD. Neurology 2000, 54:1960–1964.

    PubMed  CAS  Google Scholar 

  3. Rosengren LE, Karlsson JE, Sogren M, et al.: Neurofilament protein levels in CSF are increased in dementia. Neurology 1999, 52:1090–1093.

    PubMed  CAS  Google Scholar 

  4. Arnold SE, Han L, Clark CM, et al.: Quantitative neurohistological features of frontotemporal degeneration. Neurobiol Aging 2000, 21:913–919.

    Article  PubMed  CAS  Google Scholar 

  5. Zhukareva V, Vogelsberg-Ragaglia V, Van Deerlin VM, et al.: Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia. Ann Neurol 2001, 49:165–175. The authors provide evidence for loss of tau protein, but not mRNA expression, in HDDD2 and frontal lobe degeneration (the most common neuropathologic diagnosis for sporadic frontotemporal dementia) by using Western blot and polymerase chain reaction tests. This paper indicates a new pathomechanism of tauopathies: loss of tau expression may cause frontal lobe degeneration.

    Article  PubMed  CAS  Google Scholar 

  6. Kertesz A, Kawarai T, Rogaeva E, et al.: Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions. Neurology 2000, 54:818–827.

    PubMed  CAS  Google Scholar 

  7. Kovari E, Leuba G, Savioz A, et al.: Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease. Acta Neuropathol (Berlin) 2000, 100:421–426.

    Article  CAS  Google Scholar 

  8. Rossor MN, Revesz T, Lantos PL, Warrington EK: Semantic dementia with ubiquitin-positive tau-negative inclusion bodies. Brain 2000, 123:267–276.

    Article  PubMed  Google Scholar 

  9. Hosler BA, Siddique T, Sapp PC, et al.: Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 2000, 284:1664–1669. This large survey first indicates linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22.

    Article  PubMed  CAS  Google Scholar 

  10. Ikegami S, Harada A, Hirokawa N: Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci Lett 2000, 279:129–132. The authors proved that tau-deficient mice showed muscle weakness, hyperactivity, and learning impairment. This study indicates that loss of tau protein may cause the neurological deficits observed in frontotemporal dementia.

    Article  PubMed  CAS  Google Scholar 

  11. Takei Y, Teng J, Harada A, Hirokawa N: Defects in axonal elongation and neuronal migration in mice with disrupted tau and map1b gene. J Cell Biol 2000, 150:989–1000. This study shows that tau-/-MAP1b-/-double mutant mice develop severe hypoplastic commissural axon tract and disorganized neuronal layering abnormalities. This is the first paper indicating that tau cooperates with MAP1b to regulate microtubule organization in vivo.

    Article  PubMed  CAS  Google Scholar 

  12. D’Souza I, Poorkaj P, Hong M, et al.: Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci U S A 1999, 96:5598–5603.

    Article  PubMed  CAS  Google Scholar 

  13. Rizzini C, Goedert M, Hodges JR, et al.: Tau gene mutation K257T causes a tauopathy similar to Pick’s disease. J Neuropathol Exp Neurol. 2000, 59:990–1001.

    PubMed  CAS  Google Scholar 

  14. Murrell JR, Spillantini MG, Zolo P, et al.: Tau gene mutation G389R causes a tauopathy with abundant pick body-like inclusions and axonal deposits. J Neuropathol Exp Neurol 1999, 58:1207–1226.

    PubMed  CAS  Google Scholar 

  15. Hasegawa M, Smith MJ, Iijima M, et al.: FTDP-17 mutations N279K and S305N in tau produce increased splicing of exon 10. FEBS Lett 1999, 443:93–96.

    Article  PubMed  CAS  Google Scholar 

  16. D’Souza I, Schellenberg GD: Determinants of 4-repeat tau expression: coordination between enhancing and inhibitory splicing sequences for exon 10 inclusion. J Biol Chem 2000, 275:17700–17709.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Nacharaju P, Lewis J, Easson C, et al.: Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett 1999, 447:195–199.

    Article  PubMed  CAS  Google Scholar 

  19. Gamblin TC, King ME, Dawson H, et al.: In vitro polymerization of tau protein monitored by laser light scattering: method and application to the study of FTDP-17 mutants. Biochemistry 2000, 39:6136–6144.

    Article  PubMed  CAS  Google Scholar 

  20. Jiang Z, Cote J, Kwon JM, et al.: Aberrant splicing of tau pre-mRNA caused by intronic mutations associated with the inherited dementia frontotemporal dementia with parkinsonism linked to chromosome 17. Mol Cell Biol 2000, 20:4036–4048.

    Article  PubMed  CAS  Google Scholar 

  21. Varani L, Hasegawa M, Spillantini MG, et al.: 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, 96:8229–8234.

    Article  PubMed  CAS  Google Scholar 

  22. Arima K, Kowalska A, Hasegawa M, et al.: Two brothers with frontotemporal dementia and parkinsonism with an N279K mutation of the tau gene. Neurology 2000, 54:1787–1795.

    PubMed  CAS  Google Scholar 

  23. Delisle MB, Murrell JR, Richardson R, et al.: A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a tauopathy with dementia and supranuclear palsy. Acta Neuropathol (Berlin) 1999, 98:62–77.

    Article  CAS  Google Scholar 

  24. Spillantini MG, Yoshiyda H, Rizzini C, et al.: A norvel tau mutation (N296N) in familial dementia with swollen achromatic neurons and corticobasal inclusion bodies. Ann Neurol 2000, 48:939–943.

    Article  PubMed  CAS  Google Scholar 

  25. Stanford PM, Halliday GM, Brooks WS, et al.: Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations. Brain 2000, 123:880–893.

    Article  PubMed  Google Scholar 

  26. Yasuda M, Takamatsu J, D’Souza I, et al.: 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, 47:422–429.

    Article  PubMed  CAS  Google Scholar 

  27. Lippa CF, Zhukareve V, Kawarai T, et al.: Frontotemprotal dementia with novel tau pathology and a Glu342Val tau mutation. Ann Neurol 2000, 48:850–858.

    Article  PubMed  CAS  Google Scholar 

  28. Nasreddine ZS, Loginov M, Clark LN, et al.: 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, 45:704–715.

    Article  PubMed  CAS  Google Scholar 

  29. Bird TD, Nochlin D, Poorkaj P, et al.: A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene. Brain 1999, 122:741–756. The author’s detailed investigation of the clinical and pathologic differences in three FTDP-17 families with P301L mutation indicates that environmental, genetic, or a combination of both factors must influence phenotypic variation in the same missense mutation.

    Article  PubMed  Google Scholar 

  30. Sperfeld AD, Collatz MB, Baier H, et al.: FTDP-17: an earlyonset phenotype with parkinsonism and epileptic seizures caused by a novel mutation. Ann Neurol 1999, 46:708–715.

    Article  PubMed  CAS  Google Scholar 

  31. Bugiani O, Murrell JR, Giaccone G, et al.: Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol 1999, 58:667–677.

    PubMed  CAS  Google Scholar 

  32. Pichering-Brown S, Baker M, Yen SH, et al.: Pick’s disease is associated with mutations in the tau gene. Ann Neurol 2000, 48:859–887.

    Article  Google Scholar 

  33. van Swieten JC, Stevens M, Rosso SM, et al.: Phenotypic variation in hereditary frontotemporal dementia with tau mutations. Ann Neurol 1999, 46:617–626.

    Article  PubMed  Google Scholar 

  34. Chambers CB, Lee JM, Troncoso JC, et al.: Overexpression of four-repeat tau mRNA isoforms in progressive supranuclear palsy but not in Alzheimer’s disease. Ann Neurol 1999, 46:325–332.

    Article  PubMed  CAS  Google Scholar 

  35. Morris HR, Janssen JC, Bandmann O, et al.: The tau gene A0 polymorphism in progressive supranuclear palsy and related neurodegenerative diseases. J Neurol Neurosurg Psychiatry 1999, 66:665–667.

    Article  PubMed  CAS  Google Scholar 

  36. Ezquerra M, Pastor P, Valldeoriola F, et al.: Identification of a novel polymorphism in the promoter region of the tau gene highly associated to progressive supranuclear palsy in humans. Neurosci Lett 1999, 275:183–186.

    Article  PubMed  CAS  Google Scholar 

  37. Baker M, Litvan I, Houlden H, et al.: Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 1999, 8:711–715.

    Article  PubMed  CAS  Google Scholar 

  38. Bonifati V, Joosse M, Nicholl DJ, et al.: The tau gene in progressive supranuclear palsy: exclusion of mutations in coding exons and exon 10 splice sites, and identification of a new intronic variant of the disease-associated H1 haplotype in Italian cases. Neurosci Lett 1999, 274:61–65.

    Article  PubMed  CAS  Google Scholar 

  39. Higgins JJ, Litvan I, Nee LE, Loveless JM: A lack of the R406W tau mutation in progressive supranuclear palsy and corticobasal degeneration. Neurology 1999, 52:404–406.

    PubMed  CAS  Google Scholar 

  40. Di Maria E, Tabaton M, Vigo T, et al.: Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann Neurol 2000, 47:374–377.

    Article  PubMed  Google Scholar 

  41. Spittaels K, Van den Haute C, Van Dorpe J, et al.: Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol 1999, 155:2153–2165.

    PubMed  CAS  Google Scholar 

  42. Probst A, Gotz J, Wiederhold KH, et al.: Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol (Berlin) 2000, 99:469–481.

    Article  CAS  Google Scholar 

  43. Ishihara T, Hong M, Zhang B, et al.: Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 1999, 24:751–762.

    Article  PubMed  CAS  Google Scholar 

  44. Brion JP, Tremp G, Octave JN: Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer’s disease. Am J Pathol 1999, 154:255–270.

    PubMed  CAS  Google Scholar 

  45. Duff K, Knight H, Refolo LM, et al.: Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol Dis 2000, 7:87–98.

    Article  PubMed  CAS  Google Scholar 

  46. Ishihara T, Zhang B, Higuchi M, et al.: age dependent induction of congophilic neurofibrillary inclusions in tau transgenic mice. Am J Pathol 2001, 158:555–562.

    PubMed  CAS  Google Scholar 

  47. Lewis J, McGowan E, Rockwood J, et al.: Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 2000, 25:402–405. The authors first reported that P301L tau gene mutation causes motor and behavioral defects, as well as neurofibrillary tau tangles, in transgenic mice.

    Article  PubMed  CAS  Google Scholar 

  48. Gotz J, Chen F, Barmettler R, Nitsch RM: Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 2001, 276:529–534.

    Article  PubMed  CAS  Google Scholar 

  49. Rizzu P, Joosse M, Ravid R, et al.: Mutation-dependent aggregation of tau protein and its selective depletion from the soluble fraction in brain of P301L FTDP-17 patients. Hum Mol Genet 2000, 9:3075–3082. Biochemical data on brains from patients with FTDP-17 using antibodies specific to P301L mutant tau protein show a selective aggregation of P301L mutant tau protein resulting in insoluble deposits and the specific depletion of mutant tau protein in the soluble fraction. This indicates that the P301L mutation may cause neurodegeneration by promoting the aggregation of the mutant tau protein in human brain.

    Article  PubMed  CAS  Google Scholar 

  50. Spittaels K, Van Den Haute C, Van Dorpe J, et al.: Glycogen synthase kinase-3-beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J Biol Chem 2000, 275:41340–41349.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Center for Neurodegenerative Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3400 Spruce Street, 3rd Floor Maloney, 19104, Philadelphia, PA, USA

    Yasumasa Yoshiyama MD, PhD, Virginia M-Y Lee PhD & John Q. Trojanowski MD, PhD

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  1. Yasumasa Yoshiyama MD, PhD
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  2. Virginia M-Y Lee PhD
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  3. John Q. Trojanowski MD, PhD
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Yoshiyama, Y., Lee, V.MY. & Trojanowski, J.Q. Frontotemporal dementia and tauopathy. Curr Neurol Neurosci Rep 1, 413–421 (2001). https://doi.org/10.1007/s11910-001-0100-0

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