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Tau and α-Synuclein in Neurodegenerative Diseases

  • Chapter
Molecular Mechanisms of Neurodegenerative Diseases

Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

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Abstract

The past 2 yr have been extremely prolific in the area of neurodegenerative research, particularly with regard to diseases involving the proteins tau and synuclein. Tau aggregation in the form of filaments has long been implicated in diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), as well as others. The recent discovery of tau gene mutations in patients afflicted by a heterogeneous disease entity termed fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has provided genetic corroboration for the importance of tau in disease and opens novel avenues of investigation into the nature of tau dysfunctions that lead to the demise of neurons. The discovery of mutations in α-synuclein in familial cases of Parkinson’s disease (PD) has led to the revelation that this protein likely plays a prominent role in the etiology of several sporadic neurodegenerative disorders including PD, dementia with Lewy body (DLB) and multiple system atrophy (MSA), collectively grouped as synucleinopathies. In common with the subset of neurodegenerative diseases known as tauopathies because they are characterized by prominent filamentous tau aggregates in neurons and glia, similar fibrillary inclusions also accumulate in the brains of patients with synucleinopathies, but these inclusions are comprised predominantly of α-synuclein aggregates. In this chapter, the current knowledge of synuclein and tau proteins and their possible aberrant, malevolent role(s) in the onset and/or progression of brain diseases is reviewed.

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References

  1. Maroteaux, L., Campanelli, J. T., and Scheller, R. H. (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J. Neurosci. 8, 2804–2815.

    PubMed  CAS  Google Scholar 

  2. Shibasaki, Y., Baillie, D. A. M., St.Clair, D., and Brookes, A. J. (1995) High-resolution mapping of SNCA encoding a-synuclein, the non-Aß component of Alzheimer’s disease amyloid precursor, to human chromosome 4g21.3 to q22 by fluorescence in situ hybridization. Cytogenet.Cell Genet. 71, 54–55.

    Article  PubMed  CAS  Google Scholar 

  3. Chen, X., Rohan de Silva, H. A., Pettenati, M. J., Rao, P. N., St.George-Hyslop, P., Roses, A. D., et al. (1995) The human NACP/a-synuclein gene: chromosome assignment to 4g21.3-q22 and Tagl RFLP ananysis. Genomics 26, 425–1427.

    Article  PubMed  CAS  Google Scholar 

  4. Spillantini, M. G., Divane, A., and Goedert, M. (1995) Assignment of human a-synuclein(SNCA) and (3-synuclein(SNCB) genes to chromosomes 4q21 and 5q35. Genomics 27, 379–381.

    Article  PubMed  CAS  Google Scholar 

  5. Lavedan, C., Leroy, E., Torres, R., Dehejia, A., Dutra, A., Buchhlotz, S., et al. (1998) Genomic organization and expression of the human 3-synuclein gene (SNCB). Genomics 54, 173–175.

    Article  PubMed  CAS  Google Scholar 

  6. Ninkina, N. N., Alimova-Kost, M. V., Paterson, J. W. E., Delaney, L., Cohen, B. B., Imreh, S., et al. (1998) Organization, expression and polymorphism of the human persyn gene. Hum. Mol. Genet. 7, 1417–1424.

    Article  PubMed  CAS  Google Scholar 

  7. Lavedan, C., Leroy, E., Dehejia, A., Buchhlotz, S., Dutra, A., Nussbaum, R. L., et al. (1998) Identification, location and characterization of the human y-synuclein gene. Hum. Genet. 103, 106–112.

    Article  PubMed  CAS  Google Scholar 

  8. Surguchov, A., Surgucheva, I., Solessio, E., and Baehr, W. (1999) Synoretin—a new protein belonging to the synuclein family. Mol. Cell. Neurosci. 13, 95–103.

    Article  PubMed  CAS  Google Scholar 

  9. Uéda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M., et al. (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 90, 11282–11286.

    Article  PubMed  Google Scholar 

  10. Maroteaux, L. and Scheller, R. H. (1991) The rat brain synucleins; family of proteins transiently associated with neuronal membrane. Mol. Brain Res. 11, 335–343.

    Article  PubMed  CAS  Google Scholar 

  11. George, J. M., Jin, H., Woods, W. S., and Clayton, D. F. (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15, 361–372.

    Article  PubMed  CAS  Google Scholar 

  12. Weinreb, P. H., Zhen, W., Poon, A. W., Conway, K. A., and Lansbury, P. T. (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 35, 13709–13715.

    Article  PubMed  CAS  Google Scholar 

  13. Davidson, W. S., Jonas, A., Clayton, D. F., and George, J. M. (1998) Stabilization of a-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 273, 9443–9449.

    Article  PubMed  CAS  Google Scholar 

  14. Withers, G. S., George, J. M., Banker, G. A., and Clayton, D. F. (1997) Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. Dey. Brain Res. 99, 87–94.

    Article  CAS  Google Scholar 

  15. Jakes, R., Spillantini, M. G., and Goedert, M. (1994) Identification of two distinct synucleins from human brain. FEBS Lett. 345, 27–32.

    Article  PubMed  CAS  Google Scholar 

  16. Iwai, A., Masliah, E., Yoshimoto, M., Ge, N., Flanagan, L., Rohan de Silva, H. A., et al. (1995) The precursor protein of non-Aß component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14, 467–475.

    Article  PubMed  CAS  Google Scholar 

  17. Hashimoto, M., Yoshimoto, M., Sisk, A., Hsu, L. J., Sundsumo, M., Kittel, A., et al. (1997) NACP, a synaptic protein involved in Alzheimer’s disease, is differentially regulated in during megakaryocyte differentiation. Biochem. Biophys. Res. Commun. 237, 611–616.

    Article  PubMed  CAS  Google Scholar 

  18. Irizarry, M. C., Kim, T.-W., McNamara, M., Tanzi, R. E., George, J. M., Clayton, D. F., et al. (1996) Characterization of the precursor protein of the non-A(3 component of senile plaques (NACP) in the human central nervous system. J. Neuropathol. Exp. Neurol. 55, 889–895.

    PubMed  CAS  Google Scholar 

  19. Jensen, P. H., Nielsen, M. S., Jakes, R., Dotti, C. G., and Goedert, M. (1998) Binding of a-synuclein to brain vesicles is abolished by familial Parkinson’s disease mutation. J. Biol. Chem. 273, 26292–29294.

    Article  PubMed  CAS  Google Scholar 

  20. Jenco, J. M., Rawlingson, A., Daniels, B., and Morris, A. J. (1998) Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by a-and 3 -synucleins. Biochemistry 37, 4901–4909.

    Article  PubMed  CAS  Google Scholar 

  21. Nakajo, S., Ornata, K., Aiuchi, T., Shibayama, T., Okahashi, I., Ochiai, H., et al. (1990) Purification and characterization of a novel brain-specific 14-kDa protein. J. Neurochem. 55, 2031–2038.

    Article  PubMed  CAS  Google Scholar 

  22. Shibayama-Imazu, T., Okahashi, I., Ornata, K., Nakajo, S., Ochiai, H., Nakai, Y., et al. (1993) Cell and tissue distribution and development change of neuron specific 14 kDa protein (phosphoneuroprotein 14). Brain Res. 622, 17–25.

    Article  PubMed  CAS  Google Scholar 

  23. Nakajo, S., Shioda, S., Nakai, Y., and Nakaya, K. (1994) Localization of phosphoneuroprotein 14 (PNP 14) and its mRNA expression in rat brain determined by immunocytochemistry and in situ hybridization. Mol. Brain Res. 27, 81–86.

    Article  PubMed  CAS  Google Scholar 

  24. Shibayama-Imazu, T., Ogane, K., Hasegawa, Y., Nakajo, S., Shioda, S., Ochiai, H., et al. (1998) Distribution of PNP 14 ((3-synuclein) in neuroendocrine tissues: localization in Sertoli cells. Mol. Reprod. Dev. 50, 163–169.

    Article  PubMed  CAS  Google Scholar 

  25. Buchman, V. L., Hunter, H. J. A., Pinón, L. G. P., Thompson, J., Privalova, E. M., Ninkina, N. N., et al. (1998) Persyn, a member of the synuclein family, has a distinct pattern of expression in the developing nervous system. J. Neurosci. 18, 9335–9341.

    PubMed  CAS  Google Scholar 

  26. Ji, H., Liu, Y. E., Jia, T., Wang, M., Liu, J., Xiao, G., et al. (1997) Identification of a breast cancer-specific gene, BCSG1, by differential cDNA sequencing. Cancer Res. 57, 759–764.

    PubMed  CAS  Google Scholar 

  27. Akopian, A. N. and Wood, J. N. (1995) Peripheral nervous system-specific genes identified by substractive cDNA cloning. J. Biol. Chem. 270, 21264–21270.

    Article  PubMed  CAS  Google Scholar 

  28. Ninkina, N. N., Privalona, E. M., Pinón, L. G. P., Davies, A. M., and Buchman, V. L. (1999) Developmentally regulated expression of persyn, a member of the synuclein family, in skin. Exp. Cell. Res. 246, 308–311.

    Article  PubMed  CAS  Google Scholar 

  29. Buchman, V. L., Adu, J., Pinón, L. G. P., Ninkina, N. N., and Davies, A. M. (1998) Persyn, a member of the synuclein family, influences neurofilament network integrity. Nat. Neurosci. 1, 101–103.

    Article  PubMed  CAS  Google Scholar 

  30. Jia, T., Liu, Y. E., Liu, J., and Shi, Y. E. (1999) Stimulation of breast cancer invasion and metastasis by synuclein y. Cancer Res. 59, 742–747.

    CAS  Google Scholar 

  31. Takeda, A., Hashuimoto, M., Mallory, M., Sundsumo, M., Hansen, L., Sisk, A., et al. (1998) Abnormal distribution of the non-A(3 component of Alzheimer’s disease amyloid precursor/a-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment. Lab. Invest. 78, 1169–1177.

    PubMed  CAS  Google Scholar 

  32. Iwai, A., Yoshimoto, M., Masliah, E., and Saitoh, T. (1995) Non-An component of Alzheimer’s disease amyloid (NAC) is amyloidogenic. Biochemistry 34, 10, 139–10, 145.

    Google Scholar 

  33. Masliah, E., Iwai, A., Mallory, M., Uéda, K., and Saitoh, T. (1996) Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer’s disease. Am. J. Pathol. 148, 201–210.

    PubMed  CAS  Google Scholar 

  34. Yoshimoto, M., Iwai, A., Kang, D., Otero, D. A. C., Xia, Y., and Saitoh, T. (1995) NACP, the precursor protein of the non-amyloid (3/A4 protein (A(3) component of Alzheimer’s disease amyloid, binds Af3 and stimulates A(3 aggregation. Proc. Natl. Acad. Sci.USA 92, 9141–9145.

    Article  PubMed  CAS  Google Scholar 

  35. Xia, Y., Rohan de Silva, H. A., Rosi, B. L., Yamaoka, L. H., Rimmler, J. B., Pericak-Vance, M. A., et al. (1996) Genetic studies in Alzheimer’s disease with an NACP/a-synuclein polymorphism. Ann. Neurol. 40, 207–215.

    Article  PubMed  CAS  Google Scholar 

  36. Hellman, N. E., Grant, E. A., and Goate, A. M. (1998) Failure to replicate a protective effect of allele 2 of NACP/a -synuclein polymorphism in Alzheimer’s disease: an association study. Ann. Neurol. 44, 278–281.

    Article  PubMed  CAS  Google Scholar 

  37. Krüger, R., Kuhn, W. M. T., Woitalla, D., Graeber, M., Kösel, S., Przuntek, H., et al. (1998) Ala30Pro mutation in the gene encoding a-synuclein in Parkinson’s disease. Nat. Gen. 18, 106–108.

    Article  Google Scholar 

  38. Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., et al. (1997) Mutations in the a-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047.

    Article  PubMed  CAS  Google Scholar 

  39. Papadimitriou, A., Veletza, V., Hadjigeorgiou, G.M., Patrikiou, A., Hirano, M., and Anastasopoulos, I. (1999) Mutated a-synuclein gene in two Greek kindreds with familial PD: incomplete penetrance. Neurology 52, 651–654.

    Article  PubMed  CAS  Google Scholar 

  40. Golbe, L. I. (1999) Alpha-synuclein and Parkinson’s disease. Mov. Disorders 14, 6–9.

    Article  CAS  Google Scholar 

  41. Chan, P., Tanner, C. M., Jiang, X., and Langston, J. W. (1998) Failure to find the a-synuclein gene missense mutation (G209A) in 100 patients with younger onset Parkinson’s disease. Neurology 50, 513–514.

    Article  PubMed  CAS  Google Scholar 

  42. Parsian, A., Racette, B., Zhang, Z. H., Chakraverty, S., Rundle, M., Goate, A., et al. (1998) Mutation, sequence analysis, and association studies of a-synuclein in Parkinson’s disease. Neurology 51, 1757–1759.

    Article  PubMed  CAS  Google Scholar 

  43. Higuchi, S., Arai, H., Matsushita, S., Matsui, T., Kimpara, T., Takeda, A., et al. (1998) Mutation in the a-synuclein gene and sporadic Parkinson’s disease, Alzheimer’s disease, and dementia with Lwey bodies. Exp. Neurol. 153, 164–166.

    Article  PubMed  CAS  Google Scholar 

  44. Chan, P., Jiang, X., Forno, L. S., Di Monto, D. A., Tanner, C. M., and Langston, J. W. (1999) Absence of mutation in the coding region of the asynuclein gene in Parkinson’s disease. Neurology 50, 1136–1137.

    Article  Google Scholar 

  45. Farrer, M., Wavrant-De Vrieze, F., Crook, R., Boles, L., Perez-Tur, J., Hardy, J., et al. (1998) Low frequency of a-synuclein mutations in familial Parkinson’s disease. Ann. Neurol. 43, 394–397.

    Article  PubMed  CAS  Google Scholar 

  46. Zareparsi, S., Kay, J., Camicioli, R., Kramer, P., Nutt, J., Bird, T., et al. (1998) Analysis of the a-synuclein G209A mutation in familial Parkinson’s disease. Lancet 351, 37–38.

    Article  PubMed  CAS  Google Scholar 

  47. Hu, C.-J., Sung, S.-M., Liu, H.-C., and Chang, J.-G. (1999) No mutation of G209A in the alpha-synuclein gene in sporadic Parkinson’s disease among Taiwan Chinese. Eur. Neurol. 41, 85–87.

    Article  PubMed  CAS  Google Scholar 

  48. Vaughan, J., Durr, A., Tassin, J., Bereznai, B., Gasser, T., Bonifati, V., et al. (1998) The a-synuclein Ala53Thr mutation is not a common cause of familial Parkinson’s disease: a study of 230 European cases. Ann. Neurol. 44, 270–273.

    Article  PubMed  CAS  Google Scholar 

  49. Vaughan, J. R., Farrer, M. J., Wszolek, Z. K., Gasser, T., Dun, A., Agid, Y., et al. (1999) Sequencing of the a-synuclein gene in a large series of cases of familial Parkinson’s disease fails to reveal any further mutations. Hum. Mol. Genet. 7, 751–753.

    Article  Google Scholar 

  50. El-Agnaf, O. M. A., Curran, M. D., Wallace, A., Middleton, D., Murgatroyd, C., Curtis A., et al. (1998) Mutation screening in exons 3 and 4 of a-synuclein in sporadic Parkinson’s and sporadic and familial dementia with Lewy bodies cases. NeuroReport 9, 3925–3927.

    Article  PubMed  CAS  Google Scholar 

  51. Lincoln, S., Gwinn-Hardy, K., Goudreau, J., Chartier-Harlin, M. C., Baker, M., Mouroux, V., et al. (1999) No pathogenic mutations in the persyn gene in Parkinson’s disease. Neurosci. Lett. 259, 65–66.

    Article  PubMed  CAS  Google Scholar 

  52. Forno, L. S. (1996) Neuropathology of Parkinson’s disease. J. Neuropathol. Exp. Neurol. 55, 259–272.

    Article  PubMed  CAS  Google Scholar 

  53. Pollanen, M. S., Dickson, D. W., and Bergeron, C. (1993) Pathology and biology of the Lewy body. J. Neuropathol. Exp. Neurol. 52, 183–191.

    Article  PubMed  CAS  Google Scholar 

  54. Spillantini, M. G., Crowthier, R. A., Jakes, R., Hasegawa, M., and Goedert, M. (1998) a-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc. Natl. Acad. Sci. USA 95, 6469–6473.

    Google Scholar 

  55. Wakabayashi, K., Matsumoto, K., Takayama, K., Yoshimoto, M., and Takahashi, H. (1997) NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson’s disease. Neurosci. Lett. 239, 45–48.

    Article  PubMed  CAS  Google Scholar 

  56. Spillantini, M. G., Schmidt, M. L., Lee, V. M. Y., Trojanowski, J. Q., Jakes, R., and Goedert, M. (1997) a-Synuclein in Lewy bodies. Nature 388, 839–840.

    Google Scholar 

  57. Baba, M., Nakajo, S., Tu, P., Tornita, T., Nakaya, K., Lee, V. M. Y., et al. (1998) Aggregation of a-synuclein in Lewy bodies of sporadic Parkinson’s disease amd dementia with Lewy bodies. Am. J. Pathol. 152, 879–884.

    PubMed  CAS  Google Scholar 

  58. Irizarry, M. C., Growdon, W., Gomez-Isla, T., Newell, K., George, J. M., Clayton, D. F., et al. (1998) Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson’s disease and cortical Lewy body disease contain a-synuclein immunoreactivity. J. Neuropathol. Exp. Neurol. 57, 334–337.

    Article  PubMed  CAS  Google Scholar 

  59. Takeda, A., Mallory, M., Sundsumo, M., Honer, W., Hansen, L., and Masliah, E. (1998) Abnormal accumulation of NACP/a-synuclein in neuro-degenerative disorders. Am. J. Pathol. 152, 367–372.

    PubMed  CAS  Google Scholar 

  60. Wakabayashi, K., Hayashi, S., Kakita, A., Yamada, M., Toyoshima, Y., Yoshimoto, M., et al. (1998) Accumulation of a-synuclein is a cytopathological feature common to Lewy body disease and multiple system atropy. Acta Neuropathol. 96, 445–452.

    Article  PubMed  CAS  Google Scholar 

  61. Arima, K., Uéda, K., Sunohara, N., Hirai, S., Izumiyama, Y., Tonozuka-Uehara, H., et al. (1998) Immunoelectron-microscopic demonstration of NACP/asynuclein-epitopes on the filamentous component of Lewy bodies in Parkinson’s disease and in dementia with Lewy bodies. Brain Res. 808, 93–100.

    Article  PubMed  CAS  Google Scholar 

  62. Braak, H., Braak, E., Yilmazer, D., de Vos, R.A.I., Jansen, E. N. H., Bohl, J., et al. (1994) Amygdala pathology in Parkinson’s disease. Acta Neuropathol. 88, 493–500.

    Article  PubMed  CAS  Google Scholar 

  63. Arai, T., Uéda, K., Akiyama, H., Haga, C., Kondo, H., Kuroki, N., et al. (1999) Argyophilic glial inclusions in the midbrain of patients with Parkinson’s disease and diffuse Lewy body disease are immunopositive for NACP/a-synuclein. Neurosci. Lett. 259, 83–86.

    Article  PubMed  CAS  Google Scholar 

  64. Arawaka, S., Saito, H., Murayama, S., and Mori, H. (1998) Lewy body in neurodegeneration with brain iron accumulation type 1 is immunoreactive for a-synuclein. Neurology 51, 887–889.

    Article  PubMed  CAS  Google Scholar 

  65. Tu, P., Galvin, J. E., Baba, M., Giasson, B., Tornita, T., Leigth, S., et al. (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multple system atrophy brain contain insoluble a-synuclein. Ann. Neurol. 44, 415–422.

    Article  PubMed  CAS  Google Scholar 

  66. Wakabayashi, K., Yoshimoto, M., Tsuji, S., and Takahashi, H. (1998) aSynuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci. Lett. 249, 180–182.

    Google Scholar 

  67. Spillantini, M. G., Crowthier, R. A., Jakes, R., Cairns, N. J., Lantos, P. L., and Goedert, M. (1998) Filamentous a-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci. Lett. 251, 205–208.

    Article  PubMed  CAS  Google Scholar 

  68. Arima, K., Uéda, K., Sunohara, N., Arakawa, K., Hirai, S., Nakamura, M., et al. (1998) NACP/a-synuclein immunoreactivity in fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system atrophy. Acta Neuropathol. 96, 439–444.

    Article  PubMed  CAS  Google Scholar 

  69. Giasson, B. I., Uryu, K., Trojanowski, J. Q., and Lee, V. M. Y. (1999) Mutant and wild type human a-synucleins assemble into elongated filaments with distinct morphologies in vitro. J. Biol. Chem. 274, 7619–7622.

    Article  CAS  Google Scholar 

  70. El-Agnaf, O. M. A., Jakes, R., Curran, M. D., and Wallace, A. (1998) Effect of the mutation Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of a-synuclein protein implicated in Parkinson’s disease. FEBS Lett. 440, 67–70.

    Article  PubMed  CAS  Google Scholar 

  71. Conway, K. A., Harper, J. D., and Lansbury, P. T. (1998) Accelerated in vitro fibril formation by a mutant a-synuclein linked to early-onset Parkinson disease. Nat.Med. 11, 1318–1320.

    Article  CAS  Google Scholar 

  72. Hashimoto, M., Hsu, L. J., Sisk, A., Xia, Y., Takeda, A., Sundsmo, M., et al. (1998) Human recombinant NACP/a-synuclein is aggregated and fibrillated in vitro: relevance for Lewy body disease. Brain Res. 799, 301–306.

    Article  PubMed  CAS  Google Scholar 

  73. Narhi, L., Wood, S. J., Steavenson, S., Jiang, Y., Wu, G. M., Anafi, D., et al. (1999) Both familial Parkinson’s disease mutations accelerate a-synuclein aggregation. J. Biol. Chem. 274, 9843–9846.

    Article  PubMed  CAS  Google Scholar 

  74. Crowthier, R. A., Jakes, R., Spillantini, M. G., and Goedert, M. (1998) Synthetic filaments assembled from C-terminally truncated a-synuclein. FEBS Lett. 436, 309–312.

    Article  Google Scholar 

  75. Cleveland, D. W., Hwo, S.-Y., and Kishimoto, T. (1977) Purification of Tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J. Mol. Biol. 116, 207–225.

    Article  PubMed  CAS  Google Scholar 

  76. Neve, R. L., Harris, P., Kosik, K. S., Kurnit, D. M., and Donlon, T. A. (1986) Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubuleassociated protein 2. Brain Res. 387, 271–280.

    PubMed  CAS  Google Scholar 

  77. Andreadis, A., Brown, W. M., and Kosik, K. S. (1992) Structure and novel exons of the human tau gene. Biochemistry 31, 10626–10633.

    Article  PubMed  CAS  Google Scholar 

  78. Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D., and Crowther, R. A. (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3, 519–526.

    Article  PubMed  CAS  Google Scholar 

  79. Goedert, M., Spillantini, M. G., Potier, M. C., Ulrich, J., and Crowther, R. A. (1989) Cloning and sequencing of the cDNA encoding an isoform of micro-tubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J. 8, 393–399.

    PubMed  CAS  Google Scholar 

  80. Goedert, M. and 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 

  81. Hong, M., Zhukareva, V., Vogelsberg-Ragaglia, V., Wszolek, Z., Reed, L., Miller, B. I., et al. (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914–1917.

    Article  PubMed  CAS  Google Scholar 

  82. Goedert, M., Spillantini, M. G., and Crowther, R. A. (1992) Cloning of a big tau microtubule-associated protein characteristic of the peripheral nervous system. Proc. Natl. Acad. Sci. USA 89, 1983–1987.

    Article  PubMed  CAS  Google Scholar 

  83. Georgieff, I. S., Liem, R. K., Mellado, W., Nunez, J., and Shelanski, M. L. (1991) High molecular weight tau: preferential localization in the peripheral nervous system. J. Cell Sci. 100, 55–60.

    PubMed  CAS  Google Scholar 

  84. Taleghany, N. and Oblinger, M. M. (1992) Regional distribution and biochemical characteristics of high molecular weight tau in the nervous system. J. Neurosci. Res. 33, 257–265.

    Article  PubMed  CAS  Google Scholar 

  85. Binder, L. I., Frankfurter, A., and Rebhun, L. I. (1985) The distribution of tau in the mammalian central nervous system. J. Cell Biol. 101, 1371–1378.

    Article  PubMed  CAS  Google Scholar 

  86. Mighelli, A., Butler, M., Brown, K., and Shelanski, M. L. (1988) Light and electron microscope localization of the microtubule-associated tau protein in rat brain. J. Neurosci. 8, 1846–1851.

    Google Scholar 

  87. LoPresti, P., Szuchet, S., Papasozomenos, S. C., Zinkowski, R. P., and Binder, L. I. (1995) Functional implications for the microtubule-associated protein tau: localization in oligodendrocytes. Proc. Natl. Acad. Sci. USA 92, 10369–10373.

    Article  PubMed  CAS  Google Scholar 

  88. Tashiro, K., Hasegawa, M., Ihara, Y., and Iwatsubo, T. (1997) Somatodendritic localization of phosphorylated tau in neonatal and adult rat cerebral cortex. NeuroReport 8, 2797–2801.

    Article  PubMed  CAS  Google Scholar 

  89. Papasozomenos, S. C. and Binder, L. I. (1987) Phosphorylation determines two distinct species of tau in the central nervous system. Cell Motil. Cytoskeleton 8, 210–226.

    Article  PubMed  CAS  Google Scholar 

  90. Drechsel, D. N., Hyman, A. A., Cobb, M. H., and Kirschner, M. W. (1992) Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol. Biol. Cell 3, 1141–1154.

    PubMed  CAS  Google Scholar 

  91. Kanai, Y., Takemura, R., Oshima, T., Mori, H., Ihara, Y., Yanagisawa, M., et al. (1989) Expression of multiple tau isoforms and microtubule bundle formation in fibroblasts transfected with a single tau cDNA. J. Cell Biol. 109, 1173–1184.

    Article  PubMed  CAS  Google Scholar 

  92. Drubin, D. G. and Kirschner, M. W. (1986) Tau protein function in living cells. J. Cell Biol. 103, 2739–2746.

    Article  PubMed  CAS  Google Scholar 

  93. Bramblett, G. T., Goedert, M., Jakes, R., Merrick, S. E., Trojanowski, J. Q., and Lee, V. M. Y. (1993) Abnormal tau phosphorylation at Ser396 in Alzheimer’s disease recapitulates development and contributes to reduced microtubule binding. Neuron 10, 1089–1099.

    Article  PubMed  CAS  Google Scholar 

  94. Kanai, Y., Chen, J., and Hirokawa, N. (1992) Microtubule bundling by tau proteins in vivo: analysis of functional domains. EMBO J. 11, 3953–3960.

    PubMed  CAS  Google Scholar 

  95. Preuss, U., Biernat, J., Mandelkow, E.-M., and Mandelkow, E. (1997) The “jaws” of tau-microtubule interaction examined in CHO cells. J. Cell Sci. 110, 789–800.

    PubMed  CAS  Google Scholar 

  96. Brandt, R. and Lee, G. (1993) Functional organization of microtubule-associated protein tau. Identification of regions which affect microtubule growth, nucleation, and bundle formation in vitro. J. Biol. Chem. 268, 3414–3419.

    PubMed  CAS  Google Scholar 

  97. Himmler, A., Drechsel, D., Kirschner, M. W., and Martin, D. W. (1989) Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol. Cell. Biol. 9, 1381–1388.

    PubMed  CAS  Google Scholar 

  98. Butner, K. A. and Kirschner, M. W. (1991) Tau protein binds to microtubules through a flexible array of distributed weak sites. J. Cell Biol. 115, 717–730.

    Article  PubMed  CAS  Google Scholar 

  99. Lee, G., Neve, R. L., and Kosik, K. S. (1989) The microtubule binding domain of tau protein. Neuron 2, 1615–1624.

    Article  PubMed  CAS  Google Scholar 

  100. Ennulat, D. J., Liem, R. K., Hashim, G. A., and Shelanski, M. L. (1989) Two separate 18-amino acid domains of tau promote the polymerization of tubulin. J. Biol. Chem. 264, 5327–5330.

    PubMed  CAS  Google Scholar 

  101. Goode, B. L. and Feinstein, S. C. (1994) Identification of a novel microtubule binding and assembly domain in the developmentally regulated inter-repeat region of tau. J. Cell Biol. 124, 769–782.

    Article  PubMed  CAS  Google Scholar 

  102. Goode, B. L., Denis, P. E., Panda, D., Radeke, M. J., Miller, H. P., Wilson, L., et al. (1997) Functional interactions between the proline-rich and repeat regions of tau enhance microtubule binding and assembly. Mol. Biol. Cell 8, 353–365.

    PubMed  CAS  Google Scholar 

  103. Chau, M.-F., Radeke, M. J., de Inés, C., Barasoain, I., Kohlstaedt, L. A., and Feinstein, S. C. (1998) The microtubule-associated protein tau cross-links to two distinct sites on each a and ß tubulin monomer via separate domains. Biochemistry 37, 17692–17703.

    Article  PubMed  CAS  Google Scholar 

  104. Biernat, J., Gustke, N., Drewes, G., Mandelkow, E. M., and Mandelkow, E. (1993) Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron 11, 153–163.

    Article  PubMed  CAS  Google Scholar 

  105. Yoshida, H. and Ihara, Y. (1993) Tau in paired helical filaments is functionally distinct from fetal tau: assembly incompetence of paired helical filament-tau. J. Neurochem. 61, 1183–1186.

    Article  PubMed  CAS  Google Scholar 

  106. Lindwall, G. and Cole, R. D. (1984) Phosphorylation affects the ability of tau protein to promote microtubule assembly. J. Biol. Chem. 259, 5301–5305.

    PubMed  CAS  Google Scholar 

  107. Harada, A., Oguchi, K., Okabe, S., Kuno, J., Terada, S., Ohshima, T.,et al. (1994) Altered microtubule organization in small-caliber axons of mice lacking tau protein. Nature 369, 488–491.

    Article  PubMed  CAS  Google Scholar 

  108. Tint, I., Slaughter, T., Fischer, I., and Black, M. M. (1998) Acute inactivation of tau has no effect on dynamics of microtubules in growing axons of cultured sympathetic neurons. J. Neurosci. 18, 8660–8673.

    PubMed  CAS  Google Scholar 

  109. Mandell, J. W. and Banker, G. A. (1996) A spatial gradient of tau protein phosphorylation in nascent axons. J. Neurosci. 16, 5727–5740.

    PubMed  CAS  Google Scholar 

  110. Kempf, M., Clement, A., Faissner, A., Lee, G., and Brandt, R. (1996) Tau binds to the distal axon early in development of polarity in a microtubuleand microfilament-dependent manner. J. Neurosci. 16, 5583–5592.

    PubMed  CAS  Google Scholar 

  111. Ebneth, A., Godemann, R., Stammer, K., Illenberger, S., Trinczek, B., Mandelkow, E.-M., et al. (1998) Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implication for Alzheimer’s disease. J. Cell Biol. 143, 777–794.

    Article  PubMed  CAS  Google Scholar 

  112. Brandt, R., Léger, J., and Lee, G. (1995) Interaction of tau with the neuronal plasma membrane mediated by tau’s amino-terminal projection domain. J. Cell Biol. 131, 1327–1340.

    Article  PubMed  CAS  Google Scholar 

  113. Jenkins, S. M. and Johnson, G. V. W. (1999) Tau complexes with phospholipase C-y in situ. NeuroReport 9, 67–71.

    Article  Google Scholar 

  114. Hwang, S. C., Jhon, D.-Y., Bae, Y. S., Kim, J. H., and Rhee, S. G. (1996) Activation of phospholipase C-y by the concerted action of tau proteins and arachidonic acid. J. Biol. Chem. 271, 18342–18349.

    Article  PubMed  CAS  Google Scholar 

  115. Trojanowski, J. Q. and Lee, V. M. Y. (1995) Phosphorylation of paired helical filament tau in Alzheimer’s disease neurofibrillary lesions: focusing on phosphatases. FASEB J. 9, 1570–1576.

    PubMed  CAS  Google Scholar 

  116. Kidd, M. (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197, 192–194.

    Article  PubMed  CAS  Google Scholar 

  117. Crowther, R. A. and Wischik, C. M. (1985) Image reconstruction of the Alzheimer paired helical filament. EMBO J. 4, 3661–3665.

    PubMed  CAS  Google Scholar 

  118. Crowther, R. A. (1991) Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc. Natl. Acad. Sci. USA 88, 2288–2292.

    Article  PubMed  CAS  Google Scholar 

  119. Yagishita, S., Itoh, Y., Nan, W., and Amano, N. (1981) Reappraisal of the fine structure of Alzheimer’s neurofibrillary tangles. Acta Neuropathol. (Berl.) 54, 239–246.

    Article  CAS  Google Scholar 

  120. Goedert, M., Wischik, C. M., Crowther, R. A., Walker, J. E., and Klug, A. (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. USA 85, 4051–4055.

    Article  PubMed  CAS  Google Scholar 

  121. Kondo, J., Honda, T., Mori, H., Hamada, Y., Miura, R., Ogawara, M., et al. (1988) The carboxyl third of tau is tightly bound to paired helical filaments. Neuron 1, 827–834.

    Article  PubMed  CAS  Google Scholar 

  122. Wischik, C. M., Novak, M., Edwards, P. C., Klug, A., Tichelaar, W., and Crowther, R. A. (1988) Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc. Natl. Acad. Sci. USA 85, 4884–4888.

    Article  PubMed  CAS  Google Scholar 

  123. Kosik, K. S., Orecchio, L. D., Binder, L., Trojanowski, J. Q., Lee, V. M. Y., and Lee, G. (1988) Epitopes that span the tau molecule are shared with paired helical filaments. Neuron 1, 817–825.

    Article  PubMed  CAS  Google Scholar 

  124. Lee, V. M. Y., Balin, B. J., Otvos, L. J., and Trojanowski, J. Q. (1991) A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science 251, 675–678.

    Article  PubMed  CAS  Google Scholar 

  125. Goedert, M., Spillantini, M. G., Cairns, N. J., and Crowther, R. A. (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8, 159–168.

    Article  PubMed  CAS  Google Scholar 

  126. Morishima-Kawashima, M., Hasegawa, M., Takio, K., Suzuki, M., Yoshida, H., Titani, K., et al. (1995) Proline-directed and non-proline-directed phosphorylation of PHF-tau. J. Biol. Chem. 270, 823–829.

    Article  PubMed  CAS  Google Scholar 

  127. Hanger, D. P., Betts, J. C., Loviny, T. L. F., Blackstock, W. P., and Anderton, B. H. (1998) New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer’s disease brain using nanoelectrospray mass spectrometry. J. Neurochem. 71, 2465–2476.

    Article  PubMed  CAS  Google Scholar 

  128. Matsuo, E. S., Shin, R. W., Billingsley, M. L., Van deVoorde, A., O’Connor, M., Trojanowski, J. Q., et al. (1994) Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau. Neuron 13, 989–1002.

    Article  PubMed  CAS  Google Scholar 

  129. Billingsley, M. L. and Kincaid, R. L. (1997) Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochem. J. 323, 577–591.

    PubMed  CAS  Google Scholar 

  130. Johnson, G. V. W. and Hartigan, J. A. (1998) Tau protein in normal and Alzheimer’s disease brain: an update. Alzheimer’s Dis. Rev. 3, 125–141.

    CAS  Google Scholar 

  131. Crowther, R. A., Olesen, O. F., Smith, M. J., Jakes, R., and Goedert, M. (1994) Assembly of Alzheimer-like filaments from full-length tau protein. FEBS Lett. 337, 135–138.

    Article  PubMed  CAS  Google Scholar 

  132. Braak, E., Braak, H., and Mandelkow, E. M. (1994) A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol. (Berl.) 87, 554–567.

    Article  CAS  Google Scholar 

  133. Bancher, C., Grundke-Iqbal, I., Iqbal, K., Fried, V. A., Smith, H. T., and Wisniewski, H. M. (1991) Abnormal phosphorylation of tau precedes ubiquitination in neurofibrillary pathology of Alzheimer disease. Brain Res. 539, 11–18.

    Article  PubMed  CAS  Google Scholar 

  134. Gustke, N., Steiner, B., Mandelkow, E. M., Biernat, J., Meyer, H. E., Goedert, M., et al. (1992) The Alzheimer-like phosphorylation of tau protein reduces microtubule binding and involves Ser-Pro and Thr-Pro motifs. FEBS Lett. 307, 199–205.

    Article  PubMed  CAS  Google Scholar 

  135. Iqbal, K., Zaidi, T., Bancher, C., and Grundke-Iqbal, I. (1994) Alzheimer paired helical filaments. Restoration of the biological activity by dephosphorylation. FEBS Lett. 349, 104–108.

    Article  PubMed  CAS  Google Scholar 

  136. Goedert, M., Jakes, R., Spillantini, M. G., Hasegawa, M., Smith, M. J., and Crowther, R. A. (1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383, 550–553.

    Article  PubMed  CAS  Google Scholar 

  137. Kampers, T., Friedhoff, P., Biernat, J., Mandelkow, E. M., and Mandelkow, E. (1996) RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett. 399, 344–349.

    Article  PubMed  CAS  Google Scholar 

  138. Perez, M., Valpuesta, J. M., Medina, M., de Garcini, E. M., and Avila, J. (1996) Polymerization of tau into filaments in the presence of heparin: the minimal sequence required for tau-tau interaction. J. Neurochem. 67, 1183–1190.

    Article  PubMed  CAS  Google Scholar 

  139. Arrasate, M., Perez, M., Valpuesta, J. M., and Avila, J. (1997) Role of glycosaminoglycans in determining the helicity of paired helical filaments. Am. J. Pathol. 151, 1115–1122.

    PubMed  CAS  Google Scholar 

  140. Hasegawa, M., Crowther, R. A., Jakes, R., and Goedert, M. (1997) Alzheimer-like changes in microtubule-associated protein Tau induced by sulfated glycosaminoglycans. Inhibition of microtubule binding, stimulation of phosphorylation, and filament assembly depend on the degree of sulfation. J. Biol. Chem. 272, 33118–33124.

    Article  PubMed  CAS  Google Scholar 

  141. DeWitt, D. A., Silver, J., Canning, D. R., and Perry, G. (1993) Chondroitin sulfate proteoglycans are associated with the lesions of Alzheimer’s disease. Exp. Neurol. 121, 149–152.

    Article  PubMed  CAS  Google Scholar 

  142. Snow, A. D., Mar, H., Nochlin, D., Kresse, H., and Wight, T. N. (1992) Peripheral distribution of dermatan sulfate proteoglycans (decorin) in amyloid-containing plaques and their presence in neurofibrillary tangles of Alzheimer’s disease. J. Histochem. Cytochem. 40, 105–113.

    Article  PubMed  CAS  Google Scholar 

  143. Morishima-Kawashima, M., Hasegawa, M., Takio, K., Suzuki, M., Titani, K., and Ihara, Y. (1993) Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments. Neuron 10, 1151–1160.

    Article  PubMed  CAS  Google Scholar 

  144. Ledesma, M. D., Bonay, P., and Avila, J. (1995) tau protein from Alzheimer’s disease is glycated at its tubulin-binding domain. J. Neurochem. 65, 1658–1664.

    Google Scholar 

  145. Ledesma, M. D., Bonay, P., Colaço, C., and Avila, J. (1994) Analysis of microtubule-associated protein tau glycation in paired helical filaments. J. Biol. Chem. 269, 21614–21619.

    PubMed  CAS  Google Scholar 

  146. Wang, J. Z., Grundke-Iqbal, I., and Iqbal, K. (1996) Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer’s disease. Nat. Med. 2, 871–875.

    Article  PubMed  CAS  Google Scholar 

  147. Iwatsubo, T., Hasegawa, M., Esaki, Y., and Ihara, Y. (1992) Lack of ubiquitin immunoreactivity at both ends of neuropil threads. Am. J. Pathol. 140, 277–282.

    PubMed  CAS  Google Scholar 

  148. Foster, N. L., Wilhelmsen, K., Sima, A. A., Jones, M. Z., D’Amato, C. J., and Gilman, S. (1997) Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Ann. Neurol. 41, 706–715.

    Article  PubMed  CAS  Google Scholar 

  149. Iijima, M., Tabira, T., Poorkaj, P., Schellenberg, G. D., Trojanowski, J. Q., Lee, V. M. Y., et al. (1998) A distinct familial presenile dementia with a novel missense mutation in the tau gene. NeuroReport 10, 497–501.

    Article  Google Scholar 

  150. Spillantini, M. G., Goedert, M., Crowther, R. A., Murrell, J. R., Farlow, M. R., and 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 

  151. Spillantini, M. G., Crowther, R. A., Kamphorst, W., Heutink, P., and van Swieten, J. C. (1998) Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. Am. J. Pathol. 153, 1359–1363.

    Article  PubMed  CAS  Google Scholar 

  152. Sima, A. A., Defendini, R., Keohane, C., D’Amato, C., Foster, N. L., Parchi, P., et al. (1996) The neuropathology of chromosome 17-linked dementia. Ann. Neurol. 39, 734–743.

    Article  PubMed  CAS  Google Scholar 

  153. Reed, L. A., Schmidt, M. L., Wszolek, Z. K., Balin, B. J., Soontornniyomkij, V., Lee, V. M. Y., et al. (1998) The neuropathology of a chromosome 17-linked autosomal dominant parkinsonism and dementia (“pallido-ponto-nigral degeneration”). J. Neuropathol. Exp. Neurol. 57, 588–601.

    Article  PubMed  CAS  Google Scholar 

  154. Goedert, M., Spillantini, M. G., Crowther, R. A., Chen, S. G., Parchi, P., Tabaton, M., et al. (1999) Tau gene mutation in familial progressive subcortical gliosis. Nat. Med. 5, 454–457.

    Article  PubMed  CAS  Google Scholar 

  155. D’Souza I., Poorkaj, P., Hong, M., Nochlin, D., Lee, V. M. Y., Bird, T. D., et al. (1999) 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. USA 96, 5598–5603.

    Article  PubMed  Google Scholar 

  156. Spillantini, M. G., Crowther, R. A., and Goedert, M. (1996) Comparision of the neurofibrillary pathology in Alzheimer’s disease and familial presenile dementia with tangles. Acta Neuropathol. 92, 42–48.

    Article  PubMed  CAS  Google Scholar 

  157. Sumi, S. M., Bird, T. D., Nochlin, D., and Raskind, M. A. (1992) Familial presenile dementia with psychosis associated with cortical neurofibrillary tangles and degeneration of the amygdala. Neurology 42, 120–127.

    Article  PubMed  CAS  Google Scholar 

  158. Hasegawa, M., Smith, M. J., and 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 

  159. Rizzu, P., Van Swieten, J.C., Joosse, M., Hasegawa, M., Stevens, M., Tibben, A., et al. (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.

    Article  PubMed  CAS  Google Scholar 

  160. Arrasate, M., Pérez, M., Armas-Portela, R., and Avila, J. (1999) Polymerization of tau peptides into fibrillar structures. The effect of FTDP-17 mutations. FEBS Lett. 446, 199–202.

    Article  PubMed  CAS  Google Scholar 

  161. Nacharaju, P., Lewis, J., Easson, C., Yen, S., Hackett, J., Hutton, M., et al. (1999) Accerated filament formation from tau protein with specific FTDP-17 missence mutations. FEBS Lett. 447, 195–199.

    Article  PubMed  CAS  Google Scholar 

  162. Clark, L. N., Poorkaj, P., Wszolek, Z. K., Geschwind D. H., Nasreddine Z. S., Miller, B., et al. (1998) Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related chromosome 17-linked neurodegenerative disorders. Proc. Natl. Acad. Sci. USA 95, 13103–13107.

    Article  PubMed  CAS  Google Scholar 

  163. Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., et al. (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 

  164. Hasegawa, M., Smith, M. J., Iijima, M., Tabira, T., and Goedert, M. (1999) FTDP-17 mutations N279K and S305N in tau produce increased splicing of exon 10. FEBS Len. 443, 93–96.

    Article  CAS  Google Scholar 

  165. Senapathy, P., Shapiro, M. B., and Harris, N. L. (1990) Splice junctions, branch point sites, and exons: sequence statistics, identification, and applications to genome project. Methods Enzymol. 183, 252–278.

    Article  PubMed  CAS  Google Scholar 

  166. Xu, R., Teng, J., and Cooper, T. A. (1993) The cardiac troponin T alternative exon contains a novel purine-rich positive splicing element. Mol. Cell. Biol. 13, 3660–3674.

    PubMed  CAS  Google Scholar 

  167. Watakabe, A., Tanaka, K., and Shimura, Y. (1993) The role of exon sequences in splice site selection. Genes Dey. 7, 407–418.

    Article  CAS  Google Scholar 

  168. Lavigueur, A., La, B. H., Kornblihtt, A. R., and Chabot, B. (1993) A splicing enhancer in the human fibronectin alternate ED1 exon interacts with SR proteins and stimulates U2 snRNP binding. Genes Dey. 7, 2405–2417.

    Article  CAS  Google Scholar 

  169. Cooper, T. A. and Mattox, W. (1997) The regulation of splice-site selection, and its role in human disease. Am. J. Hum. Genet. 61, 259–266.

    Article  PubMed  CAS  Google Scholar 

  170. Si, Z. H., Rauch, D., and Stoltzfus, C. M. (1998) The exon splicing silencer in human immunodeficiency virus type 1 Tat exon 3 is bipartite and acts early in spliceosome assembly. Mol. Cell. Biol. 18, 5404–5413.

    PubMed  CAS  Google Scholar 

  171. Spillantini, M. G., Murrell, J. R., Goedert, M., Farlow, M. R., Klug, A., and 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 

  172. Rewcastle, N. B. and Ball, M. J. (1968) Electron microscopy of the inclusion bodies in Pick’s disease. Neurology 18, 1205–1213.

    Article  PubMed  CAS  Google Scholar 

  173. Delacourte, A., Sergeant, N., Wattez, A., Gauvreau, D., and Robitaille, Y. (1998) Vulnerable neuronal subsets in Alzheimer’s and Pick’s disease are distinguished by their tau isoform distribution and phosphorylation. Ann. Neurol. 43, 193–204.

    Article  PubMed  CAS  Google Scholar 

  174. Sergeant, N., David, J. P., Lefranc, D., Vermersch, P., Wattez, A., and Delacourte, A. (1997) Different distribution of phosphorylated tau protein isoforms in Alzheimer’s and Pick’s diseases. FEBS Lett. 412, 578–582.

    Article  PubMed  CAS  Google Scholar 

  175. Sergeant, N., Wattez, A., and Delacourte, A. (1999) Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusive “exon 10” isoforms. J. Neurochem. 72, 1243–1249.

    Article  PubMed  CAS  Google Scholar 

  176. Feany, M. B., Mattiace, L. A., and Dickson, D. W. (1996) Neuropathologic overlap of progressive supranuclear palsy, Pick’s disease and corticobasal degeneration. J. Neuropathol. Exp. Neurol. 55, 53–67.

    Article  PubMed  CAS  Google Scholar 

  177. Chin, S. S. M. and Goldman, J. E. (1996) Glial inclusions in CNS degenerative disease. J. Neuropathol. Exp. Neurol. 55, 499–508.

    Article  PubMed  CAS  Google Scholar 

  178. Conrad, C., Andreadis, A., Trojanowski, J. Q., Dickson, D. W., Kang, D., Chen, X., et al. (1997) Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann. Neurol. 41, 277–281.

    Article  PubMed  CAS  Google Scholar 

  179. Bennett, P., Bonifati, V., Bonuccelli, U., Colosimo, C., De Mari, M., Fabbrini, G., et al. (1998) Direct genetic evidence for involvement of tau in progressive supranuclear plasy. Neurology 51, 982–985.

    Article  PubMed  CAS  Google Scholar 

  180. Higgins, J. J., Litvan, I., Pho, L. T., Li, W., and Nee, L. E. (1998) Progressive supranuclear gaze palsy is in linkage disequilibrium with the i and not the a-synuclein gene. Neurology 50, 270–273.

    Article  PubMed  CAS  Google Scholar 

  181. Oliva, R., Tolosa, E., Ezquerra, M., Molinuevo, J. L., Valldeoriola, F., Burquera, J., et al. (1998) Significant changes in the tau AO and A3 alleles in progressive supranuclear palsy and improved genotyping by silver detection. Arch. Neurol. 55, 1122–1124.

    Article  PubMed  CAS  Google Scholar 

  182. Baker, M., Litvan, I., Houlden, H., Adamson, J., Dickson, D., Perez-Tur, J., et al. (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum. Mol. Genet. 8, 711–715.

    Article  PubMed  CAS  Google Scholar 

  183. Dumanchin, C., Camuzat, A., Campion, D., Verpillat, P., Hannequin, D., Dubois, B., et al. (1998) Segregation of a missense mutation in the microtubule-associated protein tau gene with familial frontotemporal dementia and parkinsonism. Hum. Mol. Genet. 7, 1825–1829.

    Article  PubMed  CAS  Google Scholar 

  184. Poorkaj, P., Bird, T. D., Wijsman, E., Nemens, E., Garruto, R. M., Anderson, L., et al. (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–825.

    Article  PubMed  CAS  Google Scholar 

  185. Morris, H. R., Perez-Tur, J., Janssen, J. C., Brown, J., Lees, A. J., Wood, N. W., et al. (1999) Mutation in the tau exon 10 splice site region in familial frontotemporal dementia. Ann. Neurol. 45, 270–271.

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. Benoit I. Giasson
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  2. Christina A. Wilson
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Giasson, B.I., Wilson, C.A., Trojanowski, J.Q., Lee, V.M.Y. (2001). Tau and α-Synuclein in Neurodegenerative Diseases. In: Molecular Mechanisms of Neurodegenerative Diseases. Contemporary Clinical Neuroscience. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-006-3_7

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  • Print ISBN: 978-1-61737-197-4

  • Online ISBN: 978-1-59259-006-3

  • eBook Packages: Springer Book Archive

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