Skip to main content

Advertisement

Log in

The Power and Richness of Modelling Tauopathies in Drosophila

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Tauopathies are a group of neurodegenerative disorders characterised by altered levels of phosphorylation or mutations in the neuronal microtubule protein Tau. The heterogeneous pathology of tauopathies suggests differential susceptibility of different neuronal types to wild-type and mutant Tau. The genetic power and facility of the Drosophila model has been instrumental in exploring the molecular aetiologies of tauopathies, identifying additional proteins likely contributing to neuronal dysfunction and toxicity and novel Tau phosphorylations mediating them. Importantly, recent results indicate tissue- and temporal-specific effects on dysfunction and toxicity coupled with differential effects of distinct Tau isoforms within them. Therefore, they reveal an unexpected richness of the Drosophila model that, coupled with its molecular genetic power, will likely play a significant role in our understanding of multiple tauopathies potentially leading to their differential treatment.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Bilen J, Bonini NM (2005) Drosophila as a model for human neurodegenerative disease. Annu Rev Genet 39:153–171

    Article  PubMed  CAS  Google Scholar 

  2. Marsh JL, Thompson LM (2006) Drosophila in the study of neurodegenerative disease. Neuron 52:169–178

    Article  PubMed  CAS  Google Scholar 

  3. Kretzschmar D, Hasan G, Sharma S, Heisenberg M, Benzer S (1997) The Swiss cheese mutant causes glial hyperwrapping and brain degeneration in Drosophila. J Neurosci 17(19):7425–7432

    PubMed  CAS  Google Scholar 

  4. Rogina B, Benzer S, Helfand SL (1997) Drosophila drop-dead mutations accelerate the time course of age-related markers. Proc Natl Acad Sci USA 94(12):6303–6306

    Article  PubMed  CAS  Google Scholar 

  5. Feany MB, Bender WW (2000) A Drosophila model of Parkinson’s disease. Nature 404(6776):394–398

    Article  PubMed  CAS  Google Scholar 

  6. Jackson GR, Salecker I, Dong X, Yao X, Arnheim N, Faber PW, MacDonald ME, Zipursky SL (1998) Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21(3):633–642

    Article  PubMed  CAS  Google Scholar 

  7. Warrick JM, Paulson HL, Gray-Board GL, Bui QT, Fischbeck KH, Pittman RN, Bonini NM (1998) Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93(6):939–949

    Article  PubMed  CAS  Google Scholar 

  8. Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ (2003) Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci USA 100(7):4078–4083

    Article  PubMed  CAS  Google Scholar 

  9. Pesah Y, Pham T, Burgess H, Middlebrooks B, Verstreken P, Zhou Y, Harding M, Bellen H, Mardon G (2004) Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 131(9):2183–2194

    Article  PubMed  CAS  Google Scholar 

  10. Rong YS, Golic KG (2000) Gene targeting by homologous recombination in Drosophila. Science 288(5473):2013–2018

    Article  PubMed  CAS  Google Scholar 

  11. Yang Y, Nishimura I, Imai Y, Takahashi R, Lu B (2003) Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron 37(6):911–924

    Article  PubMed  CAS  Google Scholar 

  12. Chaudhuri A, Bowling K, Funderburk C, Lawal H, Inamdar A, Wang Z, O’Donnell JM (2007) Interaction of genetic and environmental factors in a Drosophila parkinsonism model. J Neurosci 27(10):2457–2467

    Article  PubMed  CAS  Google Scholar 

  13. Coulom H, Birman S (2004) Chronic exposure to rotenone models sporadic Parkinson’s disease in Drosophila melanogaster. J Neurosci 24(48):10993–10998

    Article  PubMed  CAS  Google Scholar 

  14. Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH, Aitken A, Skoulakis EM, Orr HT, Botas J, Zoghbi HY (2003) Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113(4):457–468

    Article  PubMed  CAS  Google Scholar 

  15. Iijima-Ando K, Iijima K (2009) Transgenic Drosophila models of Alzheimer’s disease and tauopathies. Brain Struct Funct 214:245–262. doi:10.1007/s00429-009-0234-4

    Article  PubMed  CAS  Google Scholar 

  16. Khurana V (2008) Modeling tauopathy in the fruit fly Drosophila melanogaster. J Alzheimers Dis 15(4):541–553

    PubMed  CAS  Google Scholar 

  17. Newman T, Sinadinos C, Johnston A, Sealey M, Mudher A (2011) Using Drosophila models of neurodegenerative diseases for drug discovery. Expert Opin Drug Discov 6(2):129–140

    Article  CAS  Google Scholar 

  18. Heisenberg M (2003) Mushroom body memoir: from maps to models. Nat Rev Neurosci 4(4):266–275

    Article  PubMed  CAS  Google Scholar 

  19. Pitman JL, DasGupta S, Krashes MJ, Leung B, Perrat PN, Waddell S (2009) There are many ways to train a fly. Fly 3(1):3–9

    Article  PubMed  Google Scholar 

  20. Yukovic A, Wang O, Basu AC, Kraviz EA (2006) Learning and memory associated with aggression in Drosophila melanogaster. Proc Natl Acad Sci 103:17519–17524

    Article  CAS  Google Scholar 

  21. Skoulakis EM, Grammenoudi S (2006) Dunces and da Vincis: the genetics of learning and memory in Drosophila. Cell Mol Life Sci 63(9):975–988

    Article  PubMed  CAS  Google Scholar 

  22. Davis RL (2011) Traces of Drosophila memory. Neuron 70:8–19

    Article  PubMed  CAS  Google Scholar 

  23. Avila J, Lucas JJ, Perez M, Hernandez F (2004) Role of Tau protein in both physiological and pathological conditions. Physiol Rev 84(2):361–384

    Article  PubMed  CAS  Google Scholar 

  24. Delacourte A (2005) Tauopathies: recent insights into old diseases. Folia Neuropathol 43(4):244–257

    PubMed  CAS  Google Scholar 

  25. Iqbal K, Liu F, Gong CX, Grundke-Iqbal I (2010) Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 7:656–664

    Article  PubMed  CAS  Google Scholar 

  26. Lee VM-Y, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159

    Article  PubMed  CAS  Google Scholar 

  27. Cleveland DW, Hwo SY, Kirschner MW (1977) Physical and chemical properties of purified Tau factor and the role of Tau in microtubule assembly. J Mol Biol 116(2):227–247

    Article  PubMed  CAS  Google Scholar 

  28. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 72(5):1858–1862

    Article  PubMed  CAS  Google Scholar 

  29. Andreadis A, Brown WM, Kosik KS (1992) Structure and novel exons of the human Tau gene. Biochemistry 31(43):10626–10633

    Article  PubMed  CAS  Google Scholar 

  30. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein Tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3(4):519–526

    Article  PubMed  CAS  Google Scholar 

  31. Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA (1989) Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein Tau containing four tandem repeats: differential expression of Tau protein mRNAs in human brain. EMBO J 8(2):393–399

    PubMed  CAS  Google Scholar 

  32. Goedert M, Jakes R (1990) Expression of separate isoforms of human Tau protein: correlation with the Tau pattern in brain and effects on tubulin polymerization. EMBO J 9(13):4225–4230

    PubMed  CAS  Google Scholar 

  33. Kosik KS, Orecchio LD, Bakalis S, Neve RL (1989) Developmentally regulated expression of specific Tau sequences. Neuron 2(4):1389–1397

    Article  PubMed  CAS  Google Scholar 

  34. Butner KA, Kirschner MW (1991) Tau protein binds to microtubules through a flexible array of distributed weak sites. J Cell Biol 115(3):717–730

    Article  PubMed  CAS  Google Scholar 

  35. Lu M, Kosik KS (2001) Competition for microtubule-binding with dual expression of Tau missense and splice isoforms. Mol Biol Cell 12(1):171–184

    PubMed  CAS  Google Scholar 

  36. Black MM, Slaughter T, Moshiach S, Obrocka M, Fischer I (1996) Tau is enriched on dynamic microtubules in the distal region of growing axons. J Neurosci 16(11):3601–3619

    PubMed  CAS  Google Scholar 

  37. Kempf M, Clement A, Faissner A, Lee G, Brandt R (1996) Tau binds to the distal axon early in development of polarity in a microtubule- and microfilament-dependent manner. J Neurosci 16(18):5583–5592

    PubMed  CAS  Google Scholar 

  38. Baas PW, Qiang L (2005) Neuronal microtubules: when the MAP is the roadblock. Trends Cell Biol 15(4):183–187

    Article  PubMed  CAS  Google Scholar 

  39. Dixit R, Ross JL, Goldman YE, Holzbaur EL (2008) Differential regulation of dynein and kinesin motor proteins by Tau. Science 319(5866):1086–1089

    Article  PubMed  CAS  Google Scholar 

  40. Tatebayashi Y, Haque N, Tung YC, Iqbal K, Grundke-Iqbal I (2004) Role of Tau phosphorylation by glycogen synthase kinase-3beta in the regulation of organelle transport. J Cell Sci 117(Pt 9):1653–1663

    Article  PubMed  CAS  Google Scholar 

  41. Henriquez JP, Cross D, Vial C, Maccioni RB (1995) Subpopulations of Tau interact with microtubules and actin filaments in various cell types. Cell Biochem Funct 13(4):239–250

    Article  PubMed  CAS  Google Scholar 

  42. Brandt R, Leger J, Lee G (1995) Interaction of Tau with the neural plasma membrane mediated by Tau’s amino-terminal projection domain. J Cell Biol 131(5):1327–1340

    Article  PubMed  CAS  Google Scholar 

  43. Maas T, Eidenmuller J, Brandt R (2000) Interaction of Tau with the neural membrane cortex is regulated by phosphorylation at sites that are modified in paired helical filaments. J Biol Chem 275(21):15733–15740

    Article  PubMed  CAS  Google Scholar 

  44. Liu CW, Lee G, Jay DG (1999) Tau is required for neurite outgrowth and growth cone motility of chick sensory neurons. Cell Motil Cytoskeleton 43(3):232–242

    Article  PubMed  CAS  Google Scholar 

  45. Wang JZ, Liu F (2008) Microtubule-associated protein Tau in development, degeneration and protection of neurons. Prog Neurobiol 85(2):148–175

    Article  PubMed  CAS  Google Scholar 

  46. Fuster-Matanzo A, de Barreda EG, Dawson HN, Vitek MP, Avila J, Hernandez F (2009) Function of Tau protein in adult newborn neurons. FEBS Lett 583(18):3063–3068

    Article  PubMed  CAS  Google Scholar 

  47. Sergeant N, Bretteville A, Hamdane M, Caillet-Boudin ML, Grognet P, Bombois S, Blum D, Delacourte A, Pasquier F, Vanmechelen E, Schraen-Maschke S, Buée L (2008) Biochemistry of Tau in Alzheimer’s disease and related neurological disorders. Expert Rev Proteomics 5(2):207–224

    Article  PubMed  CAS  Google Scholar 

  48. Alonso AD, Diclerico J, Li B, Corbo CP, Alaniz ME, Grundke-Iqbal I, Iqbal K (2010) Phosphorylation of Tau at Thr212, Thr231 and Ser262 combined and not individually causes neurodegeneration. J Biol Chem 285:30851–30860

    Article  PubMed  CAS  Google Scholar 

  49. Qian W, Yin X, Hu W, Shi J, Gu J, Grundke-Iqbal I, Iqbal K, Gong CX, Liu F (2011) Activation of protein phosphatase 2B and hyperphosphorylation of Tau in Alzheimer’s disease. J Alzheimers Dis 23(4):617–627

    PubMed  CAS  Google Scholar 

  50. Wang JZ, Grundke-Iqbal I, Iqbal K (2007) Kinases and phosphatases and Tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25(1):59–68

    Article  PubMed  Google Scholar 

  51. Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2005) Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of Tau phosphorylation. Eur J Neurosci 22(8):1942–1950

    Article  PubMed  Google Scholar 

  52. Kosmidis S, Grammenoudi S, Papanikolopoulou K, Skoulakis EMC (2010) Differential effects of Tau on the integrity and function of neurons essential for learning in Drosophila. J Neurosci 30:464–477

    Article  PubMed  CAS  Google Scholar 

  53. Nishimura I, Yang Y, Lu B (2004) PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers Tau toxicity in Drosophila. Cell 116(5):671–682

    Article  PubMed  CAS  Google Scholar 

  54. Gong CX, Liu F, Grundke-Iqbal I, Iqbal K (2005) Post-translational modifications of Tau protein in Alzheimer’s disease. J Neural Transm 112(6):813–838

    Article  PubMed  CAS  Google Scholar 

  55. Hong M, Lee VM (1997) Insulin and insulin-like growth factor-1 regulate Tau phosphorylation in cultured human neurons. J Biol Chem 272(31):19547–19553

    Article  PubMed  CAS  Google Scholar 

  56. Hosoi T, Uchiyama M, Okumura E, Saito T, Ishiguro K, Uchida T, Okuyama A, Kishimoto T, Hisanaga S (1995) Evidence for cdk5 as a major activity phosphorylating Tau protein in porcine brain extract. J Biochem 117(4):741–749

    PubMed  CAS  Google Scholar 

  57. Zheng-Fischhofer Q, Biernat J, Mandelkow EM, Illenberger S, Godemann R, Mandelkow E (1998) Sequential phosphorylation of Tau by glycogen synthase kinase-3beta and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of antibody AT100 and requires a paired-helical-filament-like conformation. Eur J Biochem 252(3):542–552

    Article  PubMed  CAS  Google Scholar 

  58. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM (1986) Microtubule-associated protein Tau. A component of Alzheimer paired helical filaments. J Biol Chem 261(13):6084–6089

    PubMed  CAS  Google Scholar 

  59. Kosik KS, Joachim CL, Selkoe DJ (1986) Microtubule-associated protein Tau (Tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci USA 83(11):4044–4048

    Article  PubMed  CAS  Google Scholar 

  60. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33(1):95–130

    Article  PubMed  CAS  Google Scholar 

  61. Buee L, Delacourte A (1999) Comparative biochemistry of Tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick’s disease. Brain Pathol 9(4):681–693

    Article  PubMed  CAS  Google Scholar 

  62. Trojanowski JQ, Lee VM (2005) Pathological Tau: a loss of normal function or a gain in toxicity? Nat Neurosci 8(9):1136–1137

    Article  PubMed  CAS  Google Scholar 

  63. Sergeant N, Delacourte A, Buee L (2005) Tau protein as a differential biomarker of tauopathies. Biochim Biophys Acta 1739(2–3):179–197

    PubMed  CAS  Google Scholar 

  64. Sahara N, Maeda S, Takashima A (2008) Tau oligomerization: a role for Tau aggregation intermediates linked to neurodegeneration. Curr Alzheimer Res 5(6):591–598

    Article  PubMed  CAS  Google Scholar 

  65. Maeda S, Sahara N, Saito Y, Murayama M, Yoshiike Y, Kim H, Miyasaka T, Murayama S, Ikai A, Takashima A (2007) Granular Tau oligomers as intermediates of Tau filaments. Biochemistry 47(28):7393–7404

    Google Scholar 

  66. Wang YP, Biernat J, Pickhardt M, Mandelkow E, Mandelkow EM (2007) Stepwise proteolysis liberates Tau fragments that nucleate the Alzheimer-like aggregation of full-length Tau in a neuronal cell model. Proc Natl Acad Sci USA 104(24):10252–10257

    Article  PubMed  CAS  Google Scholar 

  67. Delacourte A (2001) The molecular parameters of Tau pathology. Tau as a killer and a witness. Adv Exp Med Biol 487:5–19

    Article  PubMed  CAS  Google Scholar 

  68. Iqbal K, Liu F, Gong CX, Alonso Adel C, Grundke-Iqbal I (2009) Mechanisms of Tau-induced neurodegeneration. Acta Neuropathol 118(1):53–69

    Article  PubMed  CAS  Google Scholar 

  69. Mandelkow EM, Stamer K, Vogel R, Thies E, Mandelkow E (2003) Clogging of axons by Tau, inhibition of axonal traffic and starvation of synapses. Neurobiol Aging 24(8):1079–1085

    Article  PubMed  CAS  Google Scholar 

  70. Gendron TF, Petrucelli L (2009) The role of Tau in neurodegeneration. Mol Neurodegener 4:13

    Article  PubMed  CAS  Google Scholar 

  71. Brand AH, Dormand EL (1995) The GAL4 system as a tool for unravelling the mysteries of the Drosophila nervous system. Curr Opin Neurobiol 5(5):572–578

    Article  PubMed  CAS  Google Scholar 

  72. Duffy JB (2002) GAL4 system in Drosophila: a fly geneticist’s Swiss army knife. Genesis 34:1–15

    Article  PubMed  CAS  Google Scholar 

  73. Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, Feany MB (2001) Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293(5530):711–714

    Article  PubMed  CAS  Google Scholar 

  74. Robinow S, White K (1988) The locus elav of Drosophila melanogaster is expressed in neurons at all developmental stages. Dev Biol 126(2):294–303

    Article  PubMed  CAS  Google Scholar 

  75. Dias-Santagata D, Fulga TA, Duttaroy A, Feany MB (2007) Oxidative stress mediates Tau-induced neurodegeneration in Drosophila. J Clin Invest 117(1):236–245

    Article  PubMed  CAS  Google Scholar 

  76. Davis RL (2005) Olfactory memory formation in Drosophila: from molecular to systems neuroscience. Annu Rev Neurosci 28:275–302

    Article  PubMed  CAS  Google Scholar 

  77. Papanikolopoulou K, Kosmidis S, Grammenoudi S, Skoulakis EM (2010) Phosphorylation differentiates Tau-dependent neuronal toxicity and dysfunction. Biochem Soc Trans 38(4):981–987

    Article  PubMed  CAS  Google Scholar 

  78. Thompson A, Boekhoorn K, Van Dam AM, Lucassen PJ (2008) Changes in adult neurogenesis in neurodegenerative diseases: cause or consequence? Genes Brain Behav Suppl 1:28–42

    Google Scholar 

  79. Berry RW, Quinn B, Johnson N, Cochran EJ, Ghoshal N, Binder LI (2001) Pathological glial Tau accumulations in neurodegenerative disease: review and case report. Neurochem Int 39(5–6):469–479

    Article  PubMed  CAS  Google Scholar 

  80. Ikeda K, Akiyama H, Kondo H, Haga C, Tanno E, Tokuda T, Ikeda S (1995) Thorn-shaped astrocytes: possibly secondarily induced Tau-positive glial fibrillary tangles. Acta Neuropathol 90(6):620–625

    Article  PubMed  CAS  Google Scholar 

  81. Freeman MR, Doherty J (2006) Glial cell biology in Drosophila and vertebrates. Trends Neurosci 29(2):82–90

    Article  PubMed  CAS  Google Scholar 

  82. Colodner KJ, Feany MB (2010) Glial fibrillary tangles and JAK/STAT-mediated glial and neuronal cell death in a Drosophila model of glial tauopathy. J Neurosci 30(48):16102–16113

    Article  PubMed  CAS  Google Scholar 

  83. Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 9:663–672

    Article  CAS  Google Scholar 

  84. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39(3):409–421

    Article  PubMed  CAS  Google Scholar 

  85. Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309(5733):476–481

    Article  PubMed  CAS  Google Scholar 

  86. Tully T, Quinn WG, 2 (1985) Classical conditioning and retention in normal and mutant Drosophila melanogaster. J Comp Physiol A 157(2):263–277

    Article  PubMed  CAS  Google Scholar 

  87. Mershin A, Pavlopoulos E, Fitch O, Braden BC, Nanopoulos DV, Skoulakis EM (2004) Learning and memory deficits upon TAU accumulation in Drosophila mushroom body neurons. Learn Mem 11(3):277–287

    Article  PubMed  Google Scholar 

  88. Grammenoudi S, Anezaki M, Kosmidis S, Skoulakis EMC (2008) Modeling cell and isoform type specificity of tauopathies in Drosophila. SEB Exp Biol Ser 60:39–56

    PubMed  CAS  Google Scholar 

  89. McGuire SE, Le PT, Osborn AJ, Matsumoto K, Davis RL (2003) Spatiotemporal rescue of memory dysfunction in Drosophila. Science 302(5651):1765–1768

    Article  PubMed  CAS  Google Scholar 

  90. Roman G (2004) The genetics of Drosophila transgenics. Bioessays 26(11):1243–1253

    Article  PubMed  CAS  Google Scholar 

  91. Wang JW, Imai Y, Lu B (2007) Activation of PAR-1 kinase and stimulation of Tau phosphorylation by diverse signals require the tumor suppressor protein LKB1. J Neurosci 27(3):574–581

    Article  PubMed  CAS  Google Scholar 

  92. Kimura T, Yamashita S, Fukuda T, Park JM, Murayama M, Mizoroki T, Yoshiike Y, Sahara N, Takashima A (2007) Hyperphosphorylated Tau in parahippocampal cortex impairs place learning in aged mice expressing wild-type human Tau. EMBO J 26(24):5143–5152

    Article  PubMed  CAS  Google Scholar 

  93. Comas D, Petit F, Preat T (2004) Drosophila long-term memory formation involves regulation of cathepsin activity. Nature 430(6998):407–415

    Article  CAS  Google Scholar 

  94. Ellis MC, O’Neill EM, Rubin GM (1993) Expression of Drosophila glass protein and evidence for negative regulation of its activity in non-neuronal cells by another DNA-binding protein. Development 119(3):855–865

    PubMed  CAS  Google Scholar 

  95. Moses K, Rubin GM (1991) Glass encodes a site-specific DNA-binding protein that is regulated in response to positional signals in the developing Drosophila eye. Genes Dev 5(4):583–593

    Article  PubMed  CAS  Google Scholar 

  96. Jackson GR, Wiedau-Pazos M, Sang TK, Wagle N, Brown CA, Massachi S, Geschwind DH (2002) Human wild-type Tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34(4):509–519

    Article  PubMed  CAS  Google Scholar 

  97. Iijima-Ando K, Zhao L, Gatt A, Shenton C, Iijima KA (2010) DNA damage-activated checkpoint kinase phosphorylates Tau and enhances Tau-induced neurodegeneration. Hum Mol Genet 19(10):1930–1938

    Article  PubMed  CAS  Google Scholar 

  98. Grammenoudi S, Kosmidis S, Skoulakis EM (2006) Cell type-specific processing of human Tau proteins in Drosophila. FEBS Lett 580(19):4602–4606

    Article  PubMed  CAS  Google Scholar 

  99. Steinhilb ML, Dias-Santagata D, Fulga TA, Felch DL, Feany MB (2007) Tau phosphorylation sites work in concert to promote neurotoxicity in vivo. Mol Biol Cell 18(12):5060–5068

    Article  PubMed  CAS  Google Scholar 

  100. Khurana V, Lu Y, Steinhilb ML, Oldham S, Shulman JM, Feany MB (2006) TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr Biol 16(3):230–241

    Article  PubMed  CAS  Google Scholar 

  101. Chatterjee S, Sang TK, Lawless GM, Jackson GR (2009) Dissociation of Tau toxicity and phosphorylation: role of GSK-3beta, MARK and Cdk5 in a Drosophila model. Hum Mol Genet 18(1):164–177

    Article  PubMed  CAS  Google Scholar 

  102. Yeh PA, Chien JY, Chou CC, Huang YF, Tang CY, Wang HY, Su MT (2009) Drosophila notal bristle as a novel assessment tool for pathogenic study of Tau toxicity and screening of therapeutic compounds. Biochem Biophys Res Commun 391(1):510–516

    Article  PubMed  CAS  Google Scholar 

  103. Steinhilb ML, Dias-Santagata D, Mulkearns EE, Shulman JM, Biernat J, Mandelkow EM, Feany MB (2007) S/P and T/P phosphorylation is critical for Tau neurotoxicity in Drosophila. J Neurosci Res 85(6):1271–1278

    Article  PubMed  CAS  Google Scholar 

  104. Mudher A, Shepherd D, Newman TA, Mildren P, Jukes JP, Squire A, Mears A, Drummond JA, Berg S, MacKay D, Asuni AA, Bhat R, Lovestone S (2004) GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol Psychiatry 9(5):522–530

    Article  PubMed  CAS  Google Scholar 

  105. Hirth F (2010) Drosophila melanogaster in the study of human neurodegeneration. CNS Neurol Disord Drug Targets 9:504–523

    PubMed  CAS  Google Scholar 

  106. Chee FC, Mudher A, Cuttle MF, Newman TA, MacKay D, Lovestone S, Shepherd D (2005) Over-expression of Tau results in defective synaptic transmission in Drosophila neuromuscular junctions. Neurobiol Dis 20(3):918–928

    Article  PubMed  CAS  Google Scholar 

  107. Williams DW, Tyrer M, Shepherd D (2000) Tau and Tau reporters disrupt central projections of sensory neurons in Drosophila. J Comp Neurol 428(4):630–640

    Article  PubMed  CAS  Google Scholar 

  108. Murray MJ, Merritt DJ, Brand AH, Whitington PM (1998) In vivo dynamics of axon pathfinding in the Drosophilia CNS: a time-lapse study of an identified motorneuron. J Neurobiol 37(4):607–621

    Article  PubMed  CAS  Google Scholar 

  109. Herrup K, Neve R, Ackerman SL, Copani A (2004) Divide and die: cell cycle events as triggers of nerve cell death. J Neurosci 24(42):9232–9239

    Article  PubMed  CAS  Google Scholar 

  110. Shulman JM, Feany MB (2003) Genetic modifiers of tauopathy in Drosophila. Genetics 165(3):1233–1242

    PubMed  CAS  Google Scholar 

  111. Blard O, Feuillette S, Bou J, Chaumette B, Frebourg T, Campion D, Lecourtois M (2007) Cytoskeleton proteins are modulators of mutant Tau-induced neurodegeneration in Drosophila. Hum Mol Genet 16(5):555–566

    Article  PubMed  CAS  Google Scholar 

  112. Fulga TA, Elson-Schwab I, Khurana V, Steinhilb ML, Spires TL, Hyman BT, Feany MB (2007) Abnormal bundling and accumulation of F-actin mediates Tau-induced neuronal degeneration in vivo. Nat Cell Biol 9(2):139–148

    Article  PubMed  CAS  Google Scholar 

  113. Heidary G, Fortini ME (2001) Identification and characterization of the Drosophila Tau homolog. Mech Dev 108(1–2):171–178

    Article  PubMed  CAS  Google Scholar 

  114. Tian AG, Deng WM (2009) Par-1 and Tau regulate the anterior-posterior gradient of microtubules in Drosophila oocytes. Dev Biol 327(2):458–464

    Article  PubMed  CAS  Google Scholar 

  115. Bettencourt da Cruz A, Schwarzel M, Schulze S, Niyyati M, Heisenberg M, Kretzschmar D (2005) Disruption of the MAP1B-related protein FUTSCH leads to changes in the neuronal cytoskeleton, axonal transport defects, and progressive neurodegeneration in Drosophila. Mol Biol Cell 16(5):2433–2442

    Article  PubMed  CAS  Google Scholar 

  116. Chen X, Li Y, Huang J, Cao D, Yang G, Liu W, Lu H, Guo A (2007) Study of tauopathies by comparing Drosophila and human Tau in Drosophila. Cell Tissue Res 329(1):169–178

    Article  PubMed  CAS  Google Scholar 

  117. Ubhi KK, Shaibah H, Newman TA, Shepherd D, Mudher A (2007) A comparison of the neuronal dysfunction caused by Drosophila Tau and human Tau in a Drosophila model of tauopathies. Invert Neurosci 7(3):165–171

    Article  PubMed  CAS  Google Scholar 

  118. Chee F, Mudher A, Newman TA, Cuttle M, Lovestone S, Shepherd D (2006) Overexpression of Tau results in defective synaptic transmission in Drosophila neuromuscular junctions. Biochem Soc Trans 34(Pt 1):88–90

    PubMed  CAS  Google Scholar 

  119. Sofola O, Kerr F, Rogers I, Killick R, Augustin H, Gandy C, Allen MJ, Hardy J, Lovestone S, Partridge L (2010) Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer’s disease. PLoS Genet 6(9):e1001087

    Article  PubMed  CAS  Google Scholar 

  120. Feuillette S, Miguel L, Frebourg T, Campion D, Lecourtois M (2010) Drosophila models of human tauopathies indicate that Tau protein toxicity in vivo is mediated by soluble cytosolic phosphorylated forms of the protein. J Neurochem 113(4):895–903

    Article  PubMed  CAS  Google Scholar 

  121. Cowan CM, Bossing T, Page A, Shepherd D, Mudher A (2010) Soluble hyper-phosphorylated Tau causes microtubule breakdown and functionally compromises normal Tau in vivo. Acta Neuropathol 120(5):593–604

    Article  PubMed  CAS  Google Scholar 

  122. Cowan CM, Chee F, Shepherd D, Mudher A (2010) Disruption of neuronal function by soluble hyperphosphorylated Tau in a Drosophila model of tauopathy. Biochem Soc Trans 38(2):564–570

    Article  PubMed  CAS  Google Scholar 

  123. Ghosh S, Feany MB (2004) Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases. Hum Mol Genet 13(18):2011–2018

    Article  PubMed  CAS  Google Scholar 

  124. Karsten SL, Sang TK, Gehman LT, Chatterjee S, Liu J, Lawless GM, Sengupta S, Berry RW, Pomakian J, Oh HS, Schulz C, Hui KS, Wiedau-Pazos M, Vinters HV, Binder LI, Geschwind DH, Jackson GR (2006) A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of Tau-induced neurodegeneration. Neuron 51(5):549–560

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Efthimios M. C. Skoulakis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Papanikolopoulou, K., Skoulakis, E.M.C. The Power and Richness of Modelling Tauopathies in Drosophila . Mol Neurobiol 44, 122–133 (2011). https://doi.org/10.1007/s12035-011-8193-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-011-8193-1

Keywords

Navigation