RNA and protein-dependent mechanisms in tauopathies: Consequences for therapeutic strategies

Cellular and Molecular Life Sciences

Volumn 64, Issue 13, 2007, Pages 1701-1714

  Gallo, J M ^a   Noble, W ^a   Martin, T Rodriguez ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Aggregation; Alternative splicing; Alzheimer's disease; Glycogen synthase kinase; Neurodegeneration; Phosphorylation; Tau; Tauopathies

Indexed keywords

AR A014418; GLYCOGEN SYNTHASE KINASE 3; GLYCOGEN SYNTHASE KINASE 3 INHIBITOR; IMATINIB; LITHIUM; RNA; RNA BINDING PROTEIN; SRN 003556; TAU PROTEIN; TRANSMEMBRANE CONDUCTANCE REGULATOR; TRASTUZUMAB; UNCLASSIFIED DRUG;

ALTERNATIVE RNA SPLICING; ALZHEIMER DISEASE; DRUG TARGETING; GENE MUTATION; GENETIC ASSOCIATION; GENETIC VARIABILITY; HAPLOTYPE; HUMAN; MISSENSE MUTATION; MYOTONIC DYSTROPHY; NERVE DEGENERATION; NONHUMAN; PATHOGENESIS; PROTEIN AGGREGATION; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; REVIEW; RNA PROCESSING; RNA SPLICING; TAUOPATHY;

ALTERNATIVE SPLICING; ANIMALS; HUMANS; PHOSPHORYLATION; PROTEIN CONFORMATION; RNA; TAU PROTEINS; TAUOPATHIES;

EID: 34447124582     PISSN: 1420682X     EISSN: 15691632     Source Type: Journal    
DOI: 10.1007/s00018-007-6513-4     Document Type: Review

References (160)

1. Lee, V. M., Goedert, M. and Trojanowski, J. Q. (2001) Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121-1159.
2. Williams, D. R. (2006) Tauopathies: classification and clinical update on neurodegenerative diseases associated with micro-tubule-associated protein tau. Intern. Med. J. 36, 652-660.
3. Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H. H., Pickering Brown, S., Chakraverty, S., Isaacs, A., Grover, A., Hackett, J., Adamson, J. et al. (1998) Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702-704.
4. Poorkaj, P., Bird, T. D., Wijsman, E., Nemens, E., Garruto, R. M., Anderson, L., Andreadis, A., Wiederholt, W. C., Raskind, M. and Schellenberg, G. D. (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815-825.
5. 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.
6. Avila, J., Lim, F., Moreno, F., Belmonte, C. and Cuello, A. C. (2002) Tau function and dysfunction in neurons: its role in neurodegenerative disorders. Mol. Neurobiol. 25, 213-231.
7. Buee, L., Bussiere, T., Buee-Scherrer, V., Delacourte, A. and Hof, P. R. (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res. Brain Res. Rev. 33, 95-130.
8. Avila, J., Lucas, J. J., Perez, M. and Hernandez, F. (2004) Role of tau protein in both physiological and pathological conditions. Physiol. Rev. 84, 361-384.
9. Andreadis, A. (2005) Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases. Biochim. Biophys. Acta 1739, 91-103.
10. D'Souza, I. and Schellenberg, G. D. (2005) Regulation of tau isoform expression and dementia. Biochim. Biophys. Acta 1739, 104-115.
11. Andreadis, A., Brown, W. M. and Kosik, K. S. (1992) Structure and novel exons of the human τ gene. Biochemistry 31, 10626-10633.
12. Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D. and Crowther, R. A. (1989) Multiple isoforms of human micro-tubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 3, 519-526.
13. Brandt, R., Leger, J. and Lee, G. (1995) Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain. J. Cell Biol. 131, 1327-1340.
14. Goedert, M., Spillantini, M. G. and Crowther, R. A. (1992) Cloning of the big tau microtubule-associated protein characteristic of the peripheral nervous system. Proc. Natl. Acad. Sci. USA 89, 1983-1987.
15. Couchie, D., Mavilia, C., Georgieff, I. S., Liem, R. K. H., Shelanski, M. L. and Nunez, J. (1992) Primary structure of high molecular weight tau present in the peripheral nervous system. Proc. Natl. Acad. Sci. USA 89, 4378-4381.
16. Baker, M., Litvan, I., Houlden, H., Adamson, J., Dickson, D., Perez-Tur, J., Hardy, J., Lynch, T., Bigio, E. and Hutton, M. (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum. Mol. Genet. 8, 711-715.
17. Stefansson, H., Helgason, A., Thorleifsson, G., Steinthors-dottir, V., Masson, G., Barnard, J., Baker, A., Jonasdottir, A., Ingason, A., Gudnadottir, V. G., Desnica, N., Hicks, A. et al. (2005) A common inversion under selection in Europeans. Nat. Genet. 37, 129-137.
18. Conrad, C., Andreadis, A., Trojanowski, J. Q., Dickson, D. W., Kang, D., Chen, X., Wiederholt, W., Hansen, L., Masliah, E., Thal, L. J., Katzman, R., Xia, Y. and Saitoh, T. (1997) Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann. Neurol. 41, 277-281.
19. Houlden, H., Baker, M., Morris, H. R., MacDonald, N., Pickering-Brown, S., Adamson, J., Lees, A. J., Rossor, M. N., Quinn, N. P., Kertesz, A., Khan, M. N., Hardy, J. et al. (2001) Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology. 56, 1702-1706.
20. Di Maria, E., Tabaton, M., Vigo, T., Abbruzzese, G., Bellone, E., Donati, C., Frasson, E., Marchese, R., Montagna, P., Munoz, D. G., Pramstaller, P. P., Zanusso, G. et al. (2000) Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann. Neurol. 47, 374-377.
21. Pittman, A. M., Myers, A. J., Abou-Sleiman, P., Fung, H. C., Kaleem, M., Marlowe, L., Duckworth, J., Leung, D., Williams, D., Kilford, L., Thomas, N., Morris, C. M. et al. (2005) Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J. Med. Genet. 42, 837-846.
22. Rademakers, R., Melquist, S., Cruts, M., Theuns, J., Del-Favero, J., Poorkaj, P., Baker, M., Sleegers, K., Crook, R., De Pooter, T., Bel Kacem, S., Adamson, J. et al. (2005) High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum. Mol. Genet. 14, 3281-3292.
23. Myers, A. J., Kaleem, M., Marlowe, L., Pittman, A. M., Lees, A. J., Fung, H. C., Duckworth, J., Leung, D., Gibson, A., Morris, C. M., de Silva, R. and Hardy, J. (2005) The H1c haplotype at the MAPT locus is associated with Alzheimer's disease. Hum. Mol. Genet. 14, 2399-2404.
24. Pittman, A. M., Fung, H. C. and de Silva, R. (2006) Untangling the tau gene association with neurodegenerative disorders. Hum. Mol. Genet. 15, R188-R195.
25. Laws, S. M., Friedrich, P., Diehl-Schmid, J., Muller, J., Eisele, T., Bauml, J., Forstl, H., Kurz, A. and Riemenschneider, M. (2006) Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer's disease. Mol. Psychiatry (in press).
26. Russ, C., Lovestone, S., Baker, M., Pickering-Brown, S. M., Andersen, P. M., Furlong, R., Mann, D. and Powell, J. F. (2001) The extended haplotype of the microtubule associated protein tau gene is not associated with Pick's disease. Neuro-sci. Lett. 299, 156-158.
27. Shaw-Smith, C., Pittman, A. M., Willatt, L., Martin, H., Rickman, L., Gribble, S., Curley, R., Cumming, S., Dunn, C., Kalaitzopoulos, D., Porter, K., Prigmore, E. et al. (2006) Microdeletion encompassing MAPT at chromosome 17q21.3 isassociatedwithdevelopmentaldelayandlearningdisability. Nat. Genet. 38, 1032-1037.
28. 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.
29. Hong, M., Zhukareva, V., Vogelsberg-Ragaglia, V., Wszolek, Z., Reed, L., Miller, B. I., Geschwind, D. H., Bird, T. D., McKeel, D., Goate, A., Morris, J. C., Wilhelmsen, K. C. et al. (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914-1917.
30. Yoshida, H., Crowther, R. A. and Goedert, M. (2002) Functional effects of tau gene mutations AN296 and N296H. J. Neurochem. 80, 548-551.
31. Brandt, R., Hundelt, M. and Shahani, N. (2005) Tau alteration and neuronal degeneration in tauopathies: mechanisms and models. Biochim. Biophys. Acta. 1739, 331-354.
32. Goedert, M., Jakes, R. and Crowther, R. A. (1999) Effects of frontotemporal dementia FTDP-17 mutations on heparin-induced assembly of tau filaments. FEBS Lett. 450, 306-311.
33. Lu, M. and Kosik, K. S. (2001) Competition for microtubule-binding with dual expression of tau missense and splice isoforms. Mol. Biol. Cell 12, 171-184.
34. Bunker, J. M., Kamath, K., Wilson, L., Jordan, M. A. and Feinstein, S. C. (2006) FTDP-17 mutations compromise the ability of tau to regulate microtubule dynamics in cells. J. Biol. Chem. 281, 11856-11863.
35. Utton, M. A., Connell, J., Asuni, A. A., Van Slegtenhorst, M., Hutton, M., De Silva, R., Lees, A. J., Miller, C. C. and Anderton, B. H. (2002) The slow axonal transport of the microtubule-associated protein tau and the transport rates of different isoforms and mutants in cultured neurons. J. Neuro-sci. 22, 6394-6400.
36. Lewis, J., McGowan, E., Rockwood, J., Melrose, H., Nachar-aju, P., Van Slegtenhorst, M., Gwinn-Hardy, K., Paul, M. M., Baker, M., Yu, X., Duff, K., Hardy, J. et al. (2000) Neuro-fibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25, 402-405.
37. Malkani, R., D'Souza, I., Gwinn-Hardy, K., Schellenberg, G. D., Hardy, J. and Momeni, P. (2006) A MAPT mutation in a regulatory element upstream of exon 10 causes frontotempo-ral dementia. Neurobiol. Dis. 22, 401-403.
38. Connell, J. W., Rodriguez-Martin, T., Gibb, G. M., Khan, N. M., Grierson, A. J., Hanger, D. P., Revesz, T., Anderton, B. H. and Gallo, J.-M. (2005) Quantitative analysis of tau isoform transcripts in sporadic tauopathies. Brain Res. Mol. Brain Res. 137, 104-109.
39. van Swieten, J. C., Bronner, I. F., Azmani, A., Severijnen, L. A., Kamphorst, W., Ravid, R., Rizzu, P., Willemsen, R. and Heutink, P. (2007) The AK280 mutation in MAP tau favors exon 10 skipping in vivo. J. Neuropathol. Exp. Neurol. 66, 17-25.
40. Qiang, L., Yu, W., Andreadis, A., Luo, M. and Baas, P. W. (2006) Tau protects microtubules in the axon from severing by katanin. J. Neurosci. 26, 3120-3129.
41. Ebneth, A., Godemann, R., Stamer, K., Illenberger, S., Trinczek, B. and Mandelkow, E. (1998) Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. J. Cell Biol. 143, 777-794.
42. Vershinin, M., Carter, B. C., Razafsky, D. S., King, S. J. and Gross, S. P. (2007) Multiple-motor based transport and its regulation by Tau. Proc. Natl. Acad. Sci. USA 104, 87-92.
43. Grover, A., Houlden, H., Baker, M., Adamson, J., Lewis, J., Prihar, G., Pickering-Brown, S., Duff, K. and Hutton, M. (1999) 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. 274, 15134-15143.
44. Donahue, C. P., Muratore, C., Wu, J. Y., Kosik, K. S. and Wolfe, M. S. (2006) Stabilization of the tau exon 10 stem loop alters pre-mRNA splicing. J. Biol. Chem. 281, 23302-23306.
45. 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 Lett. 443, 93-96.
46. D'Souza, I., Poorkaj, P., Hong, M., Nochlin, D., Lee, V. M., Bird, T. D. and Schellenberg, G. D. (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.
47. Jiang, Z., Tang, H., Havlioglu, N., Zhang, X., Stamm, S., Yan, R. and Wu, J. Y. (2003) Mutations in tau gene exon10 associated with FTDP-17 alter the activity of an exonic splicing enhancer to interact with Tra2β3. J. Biol. Chem. 278, 18997-19007.
48. D'Souza, I. and Schellenberg, G. D. (2006) Arginine/serine-rich protein interaction domain-dependent modulation of a tau exon 10 splicing enhancer: altered interactions and mechanisms for functionally antagonistic FTDP-17 mutations D280K and N279K. J. Biol. Chem. 281, 2460-2469.
49. Wu, J. Y., Kar, A., Kuo, D., Yu, B. and Havlioglu, N. (2006) SRp54 (SFRS11), a regulator for tau exon 10 alternative splicing identified by an expression cloning strategy. Mol. Cell Biol. 26, 6739-6747.
50. Gao, Q. S., Memmott, J., Lafyatis, R., Stamm, S., Screaton, G. and Andreadis, A. (2000) Complex regulation of tau exon 10, whose missplicing causes frontotemporal dementia. J. Neuro-chem. 74, 490-500.
51. Wang, Y., Wang, J., Gao, L., Lafyatis, R., Stamm, S. and Andreadis, A. (2005) Tau exons 2 and 10, which are misregulated in neurodegenerative diseases, are partly regulated by silencers which bind a complex comprised of SRp30c and SRp55 that either recruits or antagonizes htra2|31. J. Biol. Chem. 280, 14230-14239.
52. Hernandez, F., Perez, M., Lucas, J. J., Mata, A. M., Bhat, R. and Avila, J. (2004) Glycogen synthase kinase-3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35. Implications for Alzheimer's disease. J. Biol. Chem. 279, 3801-3806.
53. Hartmann, A. M., Rujescu, D., Giannakouros, T., Nikolakaki, E., Goedert, M., Mandelkow, E. M., Gao, Q. S., Andreadis, A. and Stamm, S. (2001) Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors. Mol. Cell Neurosci. 18, 80-90.
54. Stanford, P. M., Shepherd, C. E., Halliday, G. M., Brooks, W. S., Schofield, P. W., Brodaty, H., Martins, R. N., Kwok, J. B. and Schofield, P. R. (2003) Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia. Brain 126, 814-826.
55. D'Souza, I. and Schellenberg, G. D. (2002) Tau exon 10 expression involves a bipartite intron 10 regulatory sequence and weak 5' and 3' splice sites. J. Biol. Chem. 277, 26587-26599.
56. Kar, A., Havlioglu, N., Tarn, W. Y. and Wu, J. Y. (2006) RBM4 interacts with an intronic element and stimulates tau exon 10 inclusion. J. Biol. Chem. 281, 24479-24488.
57. Wang, J., Gao, Q. S., Wang, Y., Lafyatis, R., Stamm, S. and Andreadis, A. (2004) Tau exon 10, whose missplicing causes frontotemporal dementia, is regulated by an intricate interplay of cis elements and trans factors. J. Neurochem. 88, 1078-1090.
58. Ishizawa, K., Ksiezak-Reding, H., Davies, P., Delacourte, A., Tiseo, P., Yen, S. H. and Dickson, D. W. (2000) A double-labeling immunohistochemical study of tau exon 10 in Alzheimer's disease, progressive supranuclear palsy and Pick's disease. Acta Neuropathol. (Berl.) 100, 235-244.
59. Buee, L. and Delacourte, A. (1999) Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick's disease. Brain Pathol. 9, 681-693.
60. Takanashi, M., Mori, H., Arima, K., Mizuno, Y. and Hattori, N. (2002) Expression patterns of tau mRNA isoforms correlate with susceptible lesions in progressive supranuclear palsy and corticobasal degeneration. Brain Res. Mol. Brain Res. 104, 210-219.
61. Chambers, C. B., Lee, J. M., Troncoso, J. C., Reich, S. and Muma, N. A. (1999) Overexpression of four-repeat tau mRNA isoforms in progressive supranuclear palsy but not in Alzheimer's disease. Ann. Neurol. 46, 325-332.
62. Clark, L. N., Poorkaj, P., Wszolek, Z., Geschwind, D. H., Nasreddine, Z. S., Miller, B., Li, D., Payami, H., Awert, F., Markopoulou, K., Andreadis, A., D'Souza, I. et al. (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. USA 95, 13103-13107.
63. Gibb, G. M., De Silva, R., Revesz, T., Lees, A. J., Anderton, B. H. and Hanger, D. P. (2004) Differential involvement and heterogeneous phosphorylation of tau isoforms in progressive supranuclear palsy. Brain Res. Mol. Brain Res. 121, 95-101.
64. Boutajangout, A., Boom, A., Leroy, K. and Brion, J.-P. (2004) Expression of tau mRNA and soluble tau isoforms in affected and non-affected brain areas in Alzheimer's disease. FEBS Lett. 576, 183-189.
65. Ingelsson, M., Ramasamy, K., Cantuti-Castelvetri, I., Sko-glund, L., Matsui, T., Orne, J., Kowa, H., Raju, S., Vander-burg, C. R., Augustinack, J. C., de Silva, R., Lees, A. J. et al. (2006) No alteration in tau exon 10 alternative splicing in tangle-bearing neurons of the Alzheimer's disease brain. Acta Neuropathol. (Berl.) 112, 439-449.
66. Glatz, D. C., Rujescu, D., Tang, Y., Berendt, F. J., Hartmann, A. M., Faltraco, F., Rosenberg, C., Hulette, C., Jellinger, K., Hampel, H., Riederer, P., Moller, H. J. et al. (2005) The alternative splicing of tau exon 10 and its regulatory proteins CLK2 and TRA2-BETA1 changes in sporadic Alzheimer's disease. J. Neurochem. 96, 635-644.
67. Caffrey, T. M., Joachim, C., Paracchini, S., Esiri, M. M. and Wade-Martins, R. (2006) Haplotype-specific expression of exon 10 at the human MAPT locus. Hum. Mol. Genet. 15, 3529-3537.
68. Myers, A.J., Pittman, A.M., Zhao, A.S., Rohrer, K., Kaleem, M., Marlowe, L., Lees, A., Leung, D., McKeith, I. G., Perry, R. H., Morris, C. M., Trojanowski, J. Q. et al. (2006) The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol. Dis. 25, 561-570.
69. Ranum, L. P. and Cooper, T. A. (2006) RNA-mediated neuromuscular disorders. Annu. Rev. Neurosci. 29, 259-277.
70. Ladd, A. N., Charlet, N. and Cooper, T. A. (2001) The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. Mol. Cell Biol. 21, 1285-1296.
71. Vermersch, P., Sergeant, N., Ruchoux, M. M., Hofmann-Radvanyi, H., Wattez, A., Petit, H., Dwailly, P. and Dela-courte, A. (1996) Specific tau variants in the brains of patients with myotonic dystrophy. Neurology 47, 711-717.
72. Sergeant, N., Sablonniere, B., Schraen-Maschke, S., Ghestem, A., Maurage, C. A., Wattez, A., Vermersch, P. and Dela-courte, A. (2001) Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type I. Hum. Mol. Genet. 10, 2143-2155.
73. Jiang, H., Mankodi, A., Swanson, M. S., Moxley, R. T. and Thornton, C. A. (2004) Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum. Mol. Genet. 13, 3079-3088.
74. Leroy, O., Dhaenens, C. M., Schraen-Maschke, S., Belarbi, K., Delacourte, A., Andreadis, A., Sablonniere, B., Buee, L., Sergeant, N. and Caillet-Boudin, M. L. (2006) ETR-3 represses Tau exons 2/3 inclusion, a splicing event abnormally enhanced in myotonic dystrophy type I. J. Neurosci. Res. 84, 852-859.
75. Mackenzie, I. R., Baker, M., West, G., Woulfe, J., Qadi, N., Gass, J., Cannon, A., Adamson, J., Feldman, H., Lindholm, C., Melquist, S., Pettman, R. et al. (2006) A family with taunegative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17. Brain 129, 853-867.
76. Rosso, S. M., Kamphorst, W., de Graaf, B., Willemsen, R., Ravid, R., Niermeijer, M. F., Spillantini, M. G., Heutink, P. and van Swieten, J. C. (2001) Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21 - 22. Brain 124, 1948-1957.
77. Skibinski, G., Parkinson, N. J., Brown, J. M., Chakrabarti, L., Lloyd, S. L., Hummerich, H., Nielsen, J. E., Hodges, J. R., Spillantini, M. G., Thusgaard, T., Brandner, S., Brun, A. et al. (2005) Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37, 806-808.
78. Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E. et al. (2006) Mutations in progranulin cause tau-negative fronto-temporal dementia linked to chromosome 17. Nature 442, 916-919.
79. Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J. J., van Duijn, C., Peeters, K. et al. (2006) Null mutations in progranulin cause ubiquitin-positive frontotem-poral dementia linked to chromosome 17q21. Nature 442, 920-924.
80. Leigh, P. N., Anderton, B. H., Dodson, A., Gallo, J.-M., Swash, M. and Power, D. M. (1988) Ubiquitin deposits in anterior horn cells in motor neurone disease. Neurosci. Lett. 93, 197-203.
81. Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., McCluskey, L. F., Miller, B. L. et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130-133.
82. Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D., Tsuchiya, K., Yoshida, M., Hashizume, Y. and Oda, T. (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602-611.
83. Buratti, E., Dork, T., Zuccato, E., Pagani, F., Romano, M. and Baralle, F. E. (2001) Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J. 20, 1774-1784.
84. Ou, S. H., Wu, F., Harrich, D., Garcia-Martinez, L. F. and Gaynor, R. B. (1995) Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J. Virol. 69, 3584-3596.
85. Ule, J., Ule, A., Spencer, J., Williams, A., Hu, J. S., Cline, M., Wang, H., Clark, T., Fraser, C., Ruggiu, M., Zeeberg, B. R., Kane, D. et al. (2005) Nova regulates brain-specific splicing to shape the synapse. Nat. Genet. 37, 844-852.
86. Kalbfuss, B., Mabon, S. A. and Misteli, T. (2001) Correction of alternative splicing of tau in frontotemporal dementia and parkinsonism linked to chromosome 17. J. Biol. Chem. 276, 42986-42993.
87. Skordis, L. A., Dunckley, M. G., Yue, B., Eperon, I. C. and Muntoni, F. (2003) Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. Proc. Natl. Acad. Sci. USA 100, 4114-4119.
88. Cartegni, L. and Krainer, A. R. (2003) Correction of disease-associated exon skipping by synthetic exon-specific activators. Nat. Struct. Biol. 10, 120-125.
89. Villemaire, I, Dion, I., Elela, S. A. and Chabot, B. (2003) Reprogramming alternative pre-messenger RNA splicing through the use of protein-binding antisense oligonucleotides. I Biol. Chem. 278, 50031-50039.
90. Puttaraju, M., Jamison, S. F., Mansfield, S. G., Garcia-Blanco, M. A. and Mitchell, L. G. (1999) Spliceosome-mediated RNA trans-splicing as a tool for gene therapy. Nat. Biotechnol. 17, 246-252.
91. Rodriguez-Martin, T., Garcia-Blanco, M. A., Mansfield, S. G., Grover, A. C., Hutton, M., Yu, Q., Zhou, J., Anderton, B. H. and Gallo, J.-M. (2005) Reprogramming of tau alternative splicing by spliceosome-mediated RNA trans-splicing: Implications for tauopathies. Proc. Natl. Acad. Sci. USA 102, 15659-15664.
92. Azzouz, M., Kingsman, S. M. and Mazarakis, N. D. (2004) Lentiviral vectors for treating and modeling human CNS disorders. J. Gene Med. 6, 951-962.
93. Wong, L. F., Azzouz, M., Walmsley, L. E., Askham, Z., Wilkes, F. J., Mitrophanous, K. A., Kingsman, S. M. and Mazarakis, N. D. (2004) Transductionpatternsofpseudotyped lentiviral vectors in the nervous system. Mol. Ther. 9, 101-111.
94. Iqbal, K., Alonso Adel, C., Chen, S., Chohan, M. O., El-Akkad, E., Gong, C. X., Khatoon, S., Li, B., Liu, F., Rahman, A., Tanimukai, H. and Grundke-Iqbal, I. (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim. Biophys. Acta 1739, 198-210.
95. Stoothoff, W. H. and Johnson, G. V. (2005) Tau phosphor-ylation: physiological and pathological consequences. Bio-chim. Biophys. Acta 1739, 280-297.
96. Kopke, E., Tung, Y. C., Shaikh, S., Alonso, A. C., Iqbal, K. and Grundke-Iqbal, I. (1993) Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J. Biol. Chem. 268, 24374-24384.
97. Hanger, D. P., Betts, J. C., Loviny, T. L., 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.
98. Alonso, A., Zaidi, T., Novak, M., Grundke-Iqbal, I. and Iqbal, K. (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc. Natl. Acad. Sci. USA 98, 6923-6928.
99. Schindowski, K., Bretteville, A., Leroy, K., Begard, S., Brion, J. P., Hamdane, M. and Buee, L. (2006) Alzheimer's diseaselike tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am. J. Pathol. 169, 599-616.
100. Lee, G., Thangavel, R., Sharma, V. M., Litersky, J. M., Bhaskar, K., Fang, S. M., Do, L. H., Andreadis, A., Van Hoesen, G. and Ksiezak-Reding, H. (2004) Phosphorylation of tau by fyn: implications for Alzheimer's disease. J. Neuro-sci. 24, 2304-2312.
101. Williamson, R., Scales, T., Clark, B. R., Gibb, G., Reynolds, C. H., Kellie, S., Bird, I. N., Varndell, I. M., Sheppard, P. W., Everall, I. and Anderton, B. H. (2002) Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloid-β peptide exposure: involvement of Src family protein kinases. J. Neurosci. 22, 10-20.
102. Derkinderen, P., Scales, T. M., Hanger, D. P., Leung, K. Y., Byers, H. L., Ward, M. A., Lenz, C., Price, C., Bird, I. N., Perera, T., Kellie, S., Williamson, R. et al. (2005) Tyrosine 394 is phosphorylated in Alzheimer's paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase. J. Neurosci. 25, 6584-6593.
103. Hanger, D. P., Hughes, K., Woodgett, J. R., Brion, J.-P. and Anderton, B. H. (1992) Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localization of the kinase. Neurosci. Lett. 147, 58-62.
104. Lovestone, S., Reynolds, C. H., Latimer, D., Davis, D. R., Anderton, B. H., Gallo, J.-M., Hanger, D., Mulot, S., Marquardt, B., Stabel, S., Woodgett, J. R. and Miller, C. C. J. (1994) Alzheimer's disease-like phosphorylation of the microtubule- associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells. Curr. Biol. 4, 1077-1086.
105. Pei, J. J., Braak, E., Braak, H., Grundke-Iqbal, I., Iqbal, K., Winblad, B. and Cowburn, R. F. (1999) Distribution of active glycogen synthase kinase 3β (GSK-3β) in brains staged for Alzheimer disease neurofibrillary changes. J. Neuropathol. Exp. Neurol. 58, 1010-1019.
106. Spittaels, K., Van den Haute, C., Van Dorpe, J., Geerts, H., Mercken, M., Bruynseels, K., Lasrado, R., Vandezande, K., Laenen, I., Boon, T., Van Lint, J., Vandenheede, J. et al. (2000) Glycogen synthase kinase-3β phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J. Biol. Chem. 275, 41340-41349.
107. Lucas, J. J., Hernandez, F., Gomez-Ramos, P., Moran, M. A., Hen, R. and Avila, J. (2001) Decreased nuclear β-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3β conditional transgenic mice. EMBO J. 20, 27-39.
108. Hernandez, F., Borrell, J., Guaza, C., Avila, J. and Lucas, J. J. (2002) Spatial learning deficit in transgenic mice that conditionally over-express GSK-3β in the brain but do not form tau filaments. J. Neurochem. 83, 1529-1533.
109. Engel, T., Lucas, J. J., Gomez-Ramos, P., Moran, M. A., Avila, J. and Hernandez, F. (2006) Cooexpression of FTDP-17 tau and GSK-3β in transgenic mice induce tau polymerization and neurodegeneration. Neurobiol. Aging 27, 1258-1268.
110. Jackson, G. R., Wiedau-Pazos, M., Sang, T. K., Wagle, N., Brown, C. A., Massachi, S. and Geschwind, D. H. (2002) Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34, 509-519.
111. Alvarez, A., Toro, R., Caceres, A. and Maccioni, R. B. (1999) Inhibition of tau phosphorylating protein kinase cdk5 prevents β-amyloid-induced neuronal death. FEBS Lett. 459, 421-426.
112. Lee, M. S., Kwon, Y. T., Li, M., Peng, J., Friedlander, R. M. and Tsai, L. H. (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405, 360-364.
113. Town, T., Zolton, J., Shaffner, R., Schnell, B., Crescentini, R., Wu, Y., Zeng, J., DelleDonne, A., Obregon, D., Tan, J. and Mullan, M. (2002) p35/Cdk5 pathway mediates soluble amyloid-β peptide-induced tau phosphorylation in vitro. J. Neurosci. Res. 69, 362-372.
114. Ahlijanian, M. K., Barrezueta, N. X., Williams, R. D., Jakowski, A., Kowsz, K. P., McCarthy, S., Coskran, T., Carlo, A., Seymour, P. A., Burkhardt, J. E., Nelson, R. B. and McNeish, J. D. (2000) Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice over-expressing human p25, an activator of cdk5. Proc. Natl. Acad. Sci. USA 97, 2910-2915.
115. Bian, F., Nath, R., Sobocinski, G., Booher, R. N., Lipinski, W. J., Callahan, M. J., Pack, A., Wang, K. K. and Walker, L. C. (2002) Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice. J. Comp. Neurol. 446, 257-266.
116. Noble, W., Olm, V., Takata, K., Casey, E., Mary, O., Meyerson, J., Gaynor, K., LaFrancois, J., Wang, L., Kondo, T., Davies, P., Burns, M. etal. (2003)Cdk5isa keyfactorintau aggregation and tangle formation in vivo. Neuron 38, 555-565.
117. Cruz, J. C., Tseng, H. C., Goldman, J. A., Shih, H. and Tsai, L. H. (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibril-lary tangles. Neuron 40, 471-483.
118. Fischer, A., Sananbenesi, F., Pang, P. T., Lu, B. and Tsai, L. H. (2005) Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48, 825-838.
119. Hallows, J. L., Chen, K., DePinho, R. A. and Vincent, I. (2003) Decreased cyclin-dependent kinase 5 (cdk5) activity is accompanied by redistribution of cdk5 and cytoskeletal proteins and increased cytoskeletal protein phosphorylation in p35 null mice. J. Neurosci. 23, 10633-10644.
120. Morfini, G., Szebenyi, G., Brown, H., Pant, H. C., Pigino, G., DeBoer, S., Beffert, U. and Brady, S. T. (2004) A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons. EMBO J. 23, 2235-2245.
121. Trinczek, B., Brajenovic, M., Ebneth, A. and Drewes, G. (2004) MARK4 is a novel microtubule-associated proteins/ microtubule affinity-regulating kinase that binds to the cellular microtubule network and to centrosomes. J. Biol. Chem. 279, 5915-5923.
122. Mandelkow, E. M., Thies, E., Trinczek, B., Biernat, J. and Mandelkow, E. (2004) MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons. J. Cell Biol. 167, 99-110.
123. Nishimura, I., Yang, Y. and Lu, B. (2004) PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila. Cell 116, 671-682.
124. Shulman, J. M. and Feany, M. B. (2003) Genetic modifiers of tauopathy in Drosophila. Genetics 165, 1233-1242.
125. Fath, T., Eidenmuller, J. and Brandt, R. (2002) Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease. J. Neurosci. 22, 9733-9741.
126. Shahani, N., Subramaniam, S., Wolf, T., Tackenberg, C. and Brandt, R. (2006) Tau aggregation and progressive neuronal degeneration in the absence of changes in spine density and morphology after targeted expression of Alzheimer's disease-relevant tau constructs in organotypic hippocampal slices. J. Neurosci. 26, 6103-6114.
127. Chung, C. W., Song, Y. H., Kim, I. K., Yoon, W. J., Ryu, B. R., Jo, D. G., Woo, H. N., Kwon, Y. K., Kim, H. H., Gwag, B. J., Mook-Jung, I. H. and Jung, Y. K. (2001) Proapoptotic effects of tau cleavage product generated by caspase-3. Neurobiol. Dis. 8, 162-172.
128. Guillozet-Bongaarts, A. L., Cahill, M. E., Cryns, V. L., Reynolds, M. R., Berry, R. W. and Binder, L. I. (2006) Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo. J. Neurochem. 97, 1005-1014.
129. Fasulo, L., Ugolini, G. and Cattaneo, A. (2005) Apoptotic effect of caspase-3 cleaved tau in hippocampal neurons and its potentiation by tau FTDP-mutation N279K. J. Alzheimers Dis. 7, 3-13.
130. Gamblin, T. C., Chen, F., Zambrano, A., Abraha, A., Lagalwar, S., Guillozet, A. L., Lu, M., Fu, Y., Garcia-Sierra, F., LaPointe, N., Miller, R., Berry, R. W. et al. (2003) Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc. Natl. Acad. Sci. USA 100, 10032-10037.
131. Perez, M., Hernandez, F., Lim, F., Diaz-Nido, J. and Avila, J. (2003) Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J. Alzheimers Dis. 5, 301-308.
132. Noble, W., Planel, E., Zehr, C., Olm, V., Meyerson, J., Suleman, F., Gaynor, K., Wang, L., LaFrancois, J., Feinstein, B., Burns, M., Krishnamurthy, P. et al. (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc. Natl. Acad. Sci. USA 102, 6990-6995.
133. Bhat, R., Xue, Y., Berg, S., Hellberg, S., Ormo, M., Nilsson, Y., Radesater, A. C., Jerning, E., Markgren, P. O., Borgegard, T., Nylof, M., Gimenez-Cassina, A. et al. (2003) Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J. Biol. Chem. 278, 45937-45945.
134. Le Corre.S., Klafki, H. W., Plesnila, N., Hubinger, G., Obermeier, A., Sahagun, H., Monse, B., Seneci, P., Lewis, J., Eriksen, J., Zehr, C., Yue, M. et al. (2006) An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. Proc. Natl. Acad. Sci. USA 103, 9673-9678.
135. Phiel, C. J., Wilson, C. A., Lee, V. M. and Klein, P. S. (2003) GSK-3a regulates production of Alzheimer's disease amy-loid-β peptides. Nature 423, 435-439.
136. Jicha, G. A., Rockwood, J. M., Berenfeld, B., Hutton, M. and Davies, P. (1999) Altered conformation of recombinant frontotemporal dementia-17 mutant tau proteins. Neurosci. Lett. 260, 153-156.
137. Weaver, C. L., Espinoza, M., Kress, Y. and Davies, P. (2000) Conformational change as one of the earliest alterations of tau in Alzheimer's disease. Neurobiol. Aging 21, 719-727.
138. Jicha, G. A., Bowser, R., Kazam, I. G. and Davies, P. (1997) Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J. Neurosci. Res. 48, 128-132.
139. Terwel, D., Lasrado, R., Snauwaert, J., Vandeweert, E., Van Haesendonck, C., Borghgraef, P. and Van Leuven, F. (2005) Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axon-opathy of Tau-4R/2N transgenic mice. J. Biol. Chem. 280, 3963-3973.
140. Zheng-Fischhofer, Q., Biernat, J., Mandelkow, E. M., Ill-enberger, S., Godemann, R. and Mandelkow, E. (1998) Sequential phosphorylation of Tau by glycogen synthase kinase-3β and protein kinase A at Thr212 and Ser214
141. Alonso, A. C., Mederlyova, A., Novak, M., Grundke-Iqbal, I. and Iqbal, K. (2004) Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J. Biol. Chem. 279, 34873-34881.
142. Taylor, J. P., Hardy, J. and Fischbeck, K. H. (2002) Toxic proteins in neurodegenerative disease. Science 296, 1991-1995.
143. Braak, H. and Braak, E. (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. (Berl.) 82, 239-259.
144. Andorfer, C., Acker, C. M., Kress, Y., Hof, P. R., Duff, K. and Davies, P. (2005) Cell-cycle reentry and cell death in trans-genic mice expressing nonmutant human tau isoforms. J. Neurosci. 25, 5446-5454.
145. Santa Cruz, K., Lewis, J., Spires, T., Paulson, J., Kotilinek, L., Ingelsson, M., Guimaraes, A., DeTure, M., Ramsden, M., McGowan, E., Forster, C., Yue, M. et al. (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476-481.
146. Andorfer, C., Kress, Y., Espinoza, M., De Silva, R., Tucker, K. L., Barde, Y. A., Duff, K. and Davies, P. (2003) Hyper-phosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J. Neurochem. 86, 582-590.
147. Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S. M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q. and Lee, V. M. (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337-351.
148. Alonso Adel, C., Li, B., Grundke-Iqbal, I. and Iqbal, K. (2006) Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity. Proc. Natl. Acad. Sci. USA 103, 8864-8869.
149. Sadqi, M., Hernandez, F., Pan, U., Perez, M., Schaeberle, M. D., Avila, J. and Munoz, V. (2002) a-Helix structure in Alzheimer's disease aggregates of tau-protein. Biochemistry 41, 7150-7155.
150. Berriman, J., Serpell, L. C., Oberg, K. A., Fink, A. L., Goedert, M. and Crowther, R. A. (2003) Tau filaments from human brain and from in vitro assembly of recombinant protein show cross-beta structure. Proc. Natl. Acad. Sci. USA 100, 9034-9038.
151. Khlistunova, I., Biernat, J., Wang, Y., Pickhardt, M., von Bergen, M., Gazova, Z., Mandelkow, E. and Mandelkow, E. M. (2006) Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs. J. Biol. Chem. 281, 1205-1214.
152. Dickey, C. A., Yue, M., Lin, W. L., Dickson, D. W., Dunmore, J. H., Lee, W. C., Zehr, C., West, G., Cao, S., Clark, A. M., Caldwell, G. A., Caldwell, K. A. et al. (2006) Deletion of the ubiquitin ligase CHIP leads to the accumulation, but not the aggregation, of both endogenous phospho- and caspase-3-cleaved tau species. J. Neurosci. 26, 6985-6996.
153. Cripps, D., Thomas, S. N., Jeng, Y., Yang, F., Davies, P. and Yang, A. J. (2006) Alzheimer disease-specific conformation of hyperphosphorylated paired helical filament-Tau is polyubi-quitinated through Lys-48, Lys-11, and Lys-6 ubiquitin conjugation. J. Biol. Chem. 281, 10825-10838.
154. Shimura, H., Schwartz, D., Gygi, S. P. and Kosik, K. S. (2004) CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J. Biol. Chem. 279, 4869-4876.
155. Petrucelli, L., Dickson, D., Kehoe, K., Taylor, J., Snyder, H., Grover, A., De, L. M., McGowan, E., Lewis, J., Prihar, G., Kim, J., Dillmann, W. H. et al. (2004) CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum. Mol. Genet. 13, 703-714.
156. Sahara, N., Murayama, M., Mizoroki, T., Urushitani, M., Imai, Y., Takahashi, R., Murata, S., Tanaka, K. and Taka-shima, A. (2005) In vivo evidence of CHIP up-regulation attenuating tau aggregation. J. Neurochem. 94, 1254-1263.
157. Faustino, N. A. and Cooper, T. A. (2003) Pre-mRNA splicing and human disease. Genes Dev. 17, 419-437.
158. Garcia-Blanco, M. A., Baraniak, A. P. and Lasda, E. L. (2004) Alternative splicing in disease and therapy. Nat. Biotech-nol. 22, 535-546.
159. Gallo, J.-M., Jin, P., Thornton, C. A., Lin, H., Robertson, J., D'Souza, I. and Schlaepfer, W. W. (2005) The role of RNA and RNA processing in neurodegeneration. J. Neurosci. 25, 10372-10375.
160. Licatalosi, D. D. and Darnell, R. B. (2006) Splicing regulation in neurologic disease. Neuron 52, 93-101.