Modeling Tauopathy in the fruit fly Drosophila melanogaster.

The fruit fly Drosophila melanogaster has emerged as a powerful system in which to model human disease. This review focuses on the utility of the fly to model tau-dependent neurodegeneration, a hallmark of Alzheimer's disease and related neurodegenerative disorders. I provide a detailed description of fly tauopathy models and summarize a number of studies that demonstrate their ability to recapitulate both primary features of tauopathy, including tau-induced neurodegeneration and phosphorylation, and secondary features, including oxidative stress, cell-cycle activation and changes in the actin cytoskeleton. Important genetic and biochemical insights are discussed, and future directions proposed.

[1]  P. Hof,et al.  Cell-Cycle Reentry and Cell Death in Transgenic Mice Expressing Nonmutant Human Tau Isoforms , 2005, The Journal of Neuroscience.

[2]  D. Selkoe,et al.  Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Esther B. E. Becker,et al.  Cell cycle regulation of neuronal apoptosis in development and disease , 2004, Progress in Neurobiology.

[4]  C. Nüsslein-Volhard,et al.  Mutations affecting segment number and polarity in Drosophila , 1980, Nature.

[5]  D. Dias-Santagata,et al.  Oxidative stress mediates tau-induced neurodegeneration in Drosophila. , 2007, The Journal of clinical investigation.

[6]  D. Dickson Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect? , 2004, The Journal of clinical investigation.

[7]  Wendy Noble,et al.  Tyrosine 394 Is Phosphorylated in Alzheimer's Paired Helical Filament Tau and in Fetal Tau with c-Abl as the Candidate Tyrosine Kinase , 2005, The Journal of Neuroscience.

[8]  R. Maccioni,et al.  Subpopulations of tau interact with microtubules and actin filaments in various cell types , 1995, Cell biochemistry and function.

[9]  Xiongwei Zhu,et al.  Alzheimer's disease: the two-hit hypothesis , 2004, The Lancet Neurology.

[10]  D. Rubinsztein,et al.  Rapamycin alleviates toxicity of different aggregate-prone proteins. , 2006, Human molecular genetics.

[11]  Stephen M. Mount,et al.  The genome sequence of Drosophila melanogaster. , 2000, Science.

[12]  J. Shulman,et al.  S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila , 2007, Journal of neuroscience research.

[13]  M. Feany,et al.  Connecting cell-cycle activation to neurodegeneration in Drosophila. , 2007, Biochimica et biophysica acta.

[14]  D. Geschwind,et al.  Human Wild-Type Tau Interacts with wingless Pathway Components and Produces Neurofibrillary Pathology in Drosophila , 2002, Neuron.

[15]  G. Johnson,et al.  Tau, where are we now? , 2002, Journal of Alzheimer's disease : JAD.

[16]  D. Dias-Santagata,et al.  Tau phosphorylation sites work in concert to promote neurotoxicity in vivo. , 2007, Molecular biology of the cell.

[17]  S. Lovestone,et al.  GSK-3β inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila , 2004, Molecular Psychiatry.

[18]  Gloria Lee Tau and src family tyrosine kinases. , 2005, Biochimica et biophysica acta.

[19]  Leslie M Thompson,et al.  Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[20]  G. Jicha,et al.  A Conformation‐ and Phosphorylation‐Dependent Antibody Recognizing the Paired Helical Filaments of Alzheimer's Disease , 1997, Journal of neurochemistry.

[21]  Bin Zhang,et al.  Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Memo,et al.  Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path? , 2001, Trends in Neurosciences.

[23]  S. Jenkins,et al.  Tau complexes with phospholipase C‐γ in situ , 1998 .

[24]  D. Housman,et al.  Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila , 2001, Nature.

[25]  J. Shulman,et al.  Genetic modifiers of tauopathy in Drosophila. , 2003, Genetics.

[26]  Hyoung-Gon Lee,et al.  Oxidative imbalance in alzheimer’s disease , 2007, Molecular Neurobiology.

[27]  I. Grundke‐Iqbal,et al.  Role of protein phosphatase‐2A and ‐1 in the regulation of GSK‐3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain , 2000, FEBS letters.

[28]  B. Hyman,et al.  Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function , 2005, Science.

[29]  G. Jicha,et al.  Alz‐50 and MC‐1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau , 1997, Journal of neuroscience research.

[30]  A Hirano,et al.  Hirano bodies and related neuronal inclusions , 1994, Neuropathology and applied neurobiology.

[31]  N. Perrimon,et al.  Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. , 1993, Development.

[32]  D. Dickson,et al.  Analysis of tauopathies with transgenic mice. , 2001, Trends in molecular medicine.

[33]  H. Braak,et al.  Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease. , 2003, The American journal of pathology.

[34]  I. Vincent,et al.  Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases , 2000, Neurobiology of Aging.

[35]  D. Dickson,et al.  Neurodegenerative disorders with extensive tau pathology: A comparative study and review , 1996, Annals of neurology.

[36]  Koichi M Iijima,et al.  Drosophila models of Alzheimer's amyloidosis: the challenge of dissecting the complex mechanisms of toxicity of amyloid-beta 42. , 2008, Journal of Alzheimer's disease : JAD.

[37]  G. Johnson,et al.  Tau protein in normal and Alzheimer's disease brain. , 1999, Journal of Alzheimer's disease : JAD.

[38]  C. Cotman,et al.  Caspase-9 Activation and Caspase Cleavage of tau in the Alzheimer's Disease Brain , 2002, Neurobiology of Disease.

[39]  Ronald L. Davis,et al.  Altered Representation of the Spatial Code for Odors after Olfactory Classical Conditioning Memory Trace Formation by Synaptic Recruitment , 2004, Neuron.

[40]  G. Perry,et al.  Alzheimer disease and the role of free radicals in the pathogenesis of the disease. , 2008, CNS & neurological disorders drug targets.

[41]  K. Herrup,et al.  DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease , 2001, The Journal of Neuroscience.

[42]  B. Winblad,et al.  Levels of mTOR and its downstream targets 4E‐BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain , 2005, The FEBS journal.

[43]  G. V. Van Hoesen,et al.  Phosphorylation of Tau by Fyn: Implications for Alzheimer's Disease , 2004, The Journal of Neuroscience.

[44]  Joshua M. Shulman,et al.  Tauopathy in Drosophila: Neurodegeneration Without Neurofibrillary Tangles , 2001, Science.

[45]  George Perry,et al.  The Role of Mitogen-Activated Protein Kinase Pathways in Alzheimer’s Disease , 2002, Neurosignals.

[46]  D. Nanopoulos,et al.  Learning and memory deficits upon TAU accumulation in Drosophila mushroom body neurons. , 2004, Learning & memory.

[47]  N. Plesnila,et al.  An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[48]  S. Ackerman,et al.  Oxidative stress, cell cycle, and neurodegeneration. , 2003, The Journal of clinical investigation.

[49]  D. Selkoe Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[50]  B. Winblad,et al.  Phosphorylated eukaryotic translation factor 4E is elevated in Alzheimer brain , 2004, Neuroreport.

[51]  K. Herrup,et al.  Ectopic Cell Cycle Events Link Human Alzheimer's Disease and Amyloid Precursor Protein Transgenic Mouse Models , 2006, The Journal of Neuroscience.

[52]  Patrick R. Hof,et al.  Tau protein isoforms, phosphorylation and role in neurodegenerative disorders 1 1 These authors contributed equally to this work. , 2000, Brain Research Reviews.

[53]  E. Masliah,et al.  Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer's Disease , 2005, Science.

[54]  Nancy M Bonini,et al.  Drosophila as a model for human neurodegenerative disease. , 2005, Annual review of genetics.

[55]  Leslie Michels Thompson,et al.  Drosophila in the Study of Neurodegenerative Disease , 2006, Neuron.

[56]  S. Lovestone,et al.  Over-expression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions , 2005, Neurobiology of Disease.

[57]  D. Selkoe Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[58]  D. Campion,et al.  Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila. , 2007, Human molecular genetics.

[59]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[60]  K. Lu,et al.  Pinning down phosphorylated tau and tauopathies. , 2005, Biochimica et biophysica acta.

[61]  Tudor A. Fulga,et al.  Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo , 2007, Nature Cell Biology.

[62]  J. Shulman,et al.  TOR-Mediated Cell-Cycle Activation Causes Neurodegeneration in a Drosophila Tauopathy Model , 2006, Current Biology.

[63]  B. Lu,et al.  PAR-1 Kinase Plays an Initiator Role in a Temporally Ordered Phosphorylation Process that Confers Tau Toxicity in Drosophila , 2004, Cell.

[64]  Miratul M. K. Muqit,et al.  Modelling neurodegenerative diseases in Drosophila: a fruitful approach? , 2002, Nature Reviews Neuroscience.

[65]  E. Mandelkow,et al.  Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity. , 2002, Molecular biology of the cell.