Skip to main content

Advertisement

SpringerLink
Log in

Understanding and treating neurodegeneration: insights from the flies

  • Review article
  • Published:
AGE Aims and scope Submit manuscript

Abstract

Drosophila has recently emerged as a model system for studying mechanisms of neurodegeneration. Genetic models for most of the major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), polyglutamine diseases, and tauopathies, have been successfully established. Pharmacological models of some of these diseases have also been created. Genetic modifier screens using these models have uncovered previously implicated mechanisms and molecules as well as novel ones. Fly models have turned out to be excellent system for the in vivo testing of therapeutic potentials of candidate compounds. It is anticipated that further exploration of the fly models will not only provide novel insights into mechanisms of neurodegeneration but also lead to the development of rational treatment of those debilitating degenerative diseases.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Akassoglou K, Malester B, Xu J, Tessarollo L, Rosenbluth J and Chao MV (2004) Brain-specific deletion of neuropathy target esterase/swisscheese results in neurodegeneration. Proc Natl Acad Sci USA 101: 5075–5080

    Article  CAS  PubMed  Google Scholar 

  • Albers DS and Beal MF (2000) Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease. J Neural Transm Suppl 59: 133–154

    CAS  PubMed  Google Scholar 

  • Augustinack JC, Schneider A, Mandelkow EM and Hyman BT (2002) Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease. Acta Neuropathol (Berl) 103: 26–35

    Article  CAS  Google Scholar 

  • Auluck PK and Bonini NM (2002) Pharmacological prevention of Parkinson disease in Drosophila. Nat Med 8: 1185–1186

    Article  CAS  PubMed  Google Scholar 

  • Auluck PK, Chan HY, Trojanowski JQ, Lee VM and Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295: 865–868

    Article  CAS  PubMed  Google Scholar 

  • Baumann K, Mandelkow EM, Biernat J, Piwnica-Worms H and Mandelkow E (1993) Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett 336: 417–424

    Article  CAS  PubMed  Google Scholar 

  • Beal MF (2001) Experimental models of Parkinson's disease. Nat Rev Neurosci 2: 325–334

    Article  CAS  PubMed  Google Scholar 

  • Bertoli-Avella AM, Oostra BA and Heutink P (2004) Chasing genes in Alzheimer's and Parkinson's disease. Hum Genet 114: 413–438

    Article  CAS  PubMed  Google Scholar 

  • Betarbet R, Sherer TB and Greenamyre JT (2002) Animal models of Parkinson's disease. Bioessays 24: 308–318

    Article  CAS  PubMed  Google Scholar 

  • Biernat J, Wu YZ, Timm T, Zheng-Fischhofer Q, Mandelkow E and Meijer L et al. (2002) Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity. Mol Biol Cell 13: 4013–4028

    Article  CAS  PubMed  Google Scholar 

  • Billingsley ML and Kincaid RL (1997) Regulated phosphorylation and dephosphorylation of tau protein: Effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochem J 323(Pt 3): 577–591

    CAS  PubMed  Google Scholar 

  • Bohm H, Brinkmann V, Drab M, Henske A and Kurzchalia TV (1997) Mammalian homologues of C. elegans PAR-1 are asymmetrically localized in epithelial cells and may influence their polarity. Curr Biol 7: 603–606

    Article  CAS  PubMed  Google Scholar 

  • Bonifati V, Rizzu P, Squitieri F, Krieger E, Vanacore N and van Swieten JC et al. (2003) DJ-1( PARK7), a novel gene for autosomal recessive, early onset Parkinsonism. Neurol Sci 24: 159–160

    Article  CAS  PubMed  Google Scholar 

  • Bonini NM and Fortini ME (2003) Human neurodegenerative disease modeling using Drosophila. Annu Rev Neurosci 26: 627–656

    Article  CAS  PubMed  Google Scholar 

  • Braak H and Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (Berl) 82: 239–259

    Article  CAS  Google Scholar 

  • Canet-Aviles RM, Wilson MA, Miller DW, Ahmad R, McLendon C and Bandyopadhyay S et al. (2004) The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine–sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci USA 101: 9103–9108

    Article  CAS  PubMed  Google Scholar 

  • Chan HY, Warrick JM, Andriola I, Merry D and Bonini NM (2002) Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum Mol Genet 11: 2895–2904

    Article  CAS  PubMed  Google Scholar 

  • Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD and Fernandez MH et al. (2003) Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113: 457–468

    Article  CAS  PubMed  Google Scholar 

  • Cleveland DW, Hwo SY and Kirschner MW (1977) Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol 116: 207–225

    Article  CAS  PubMed  Google Scholar 

  • Coulom H and Birman S (2004) Chronic exposure to rotenone models sporadic Parkinson's disease in Drosophila melanogaster. J Neurosci 24: 10993–10998

    Article  CAS  PubMed  Google Scholar 

  • Cox DN, Lu B, Sun TQ, Williams LT and Jan YN (2001) Drosophila par-1 is required for oocyte differentiation and microtubule organization. Curr Biol 11: 75–87

    Article  CAS  PubMed  Google Scholar 

  • Cummings CJ, Reinstein E, Sun Y, Antalffy B, Jiang Y and Ciechanover A et al. (1999) Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24: 879–892

    Article  CAS  PubMed  Google Scholar 

  • Davies P (2000) A very incomplete comprehensive theory of Alzheimer's disease. Ann NY Acad Sci 924: 8–16

    Article  CAS  PubMed  Google Scholar 

  • Dawson TM and Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson's disease. Science 302: 819–822

    Article  CAS  PubMed  Google Scholar 

  • De Strooper B (2003) Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 38: 9–12

    Article  PubMed  Google Scholar 

  • Dexter DT, Sian J, Rose S, Hindmarsh JG, Mann VM and Cooper JM et al. (1994) Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease. Ann Neurol 35: 38–44

    Article  CAS  PubMed  Google Scholar 

  • Dong Z, Wolfer DP, Lipp HP and Bueler H (2005) Hsp70 gene transfer by adeno-associated virus inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease. Mol Ther 11: 80–88

    Article  CAS  PubMed  Google Scholar 

  • Drewes G, Ebneth A, Preuss U, Mandelkow EM and Mandelkow E (1997) MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89: 297–308

    Article  CAS  PubMed  Google Scholar 

  • Driscoll M and Gerstbrein B (2003) Dying for a cause: Invertebrate genetics takes on human neurodegeneration. Nat Rev Genet 4: 181–194

    Article  CAS  PubMed  Google Scholar 

  • Dunnett SB and Bjorklund A (1999) Prospects for new restorative and neuroprotective treatments in Parkinson's disease. Nature 399: A32–A39

    Article  CAS  PubMed  Google Scholar 

  • Emamian ES, Kaytor MD, Duvick LA, Zu T, Tousey SK and Zoghbi HY et al. (2003) Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 38: 375–387

    Article  CAS  PubMed  Google Scholar 

  • Feany MB and Bender WW (2000) A Drosophila model of Parkinson's disease. Nature 404: 394–398

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Funez P, Nino-Rosales ML, de Gouyon B, She WC, Luchak JM and Martinez P et al. (2000) Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408: 101–106

    Article  CAS  PubMed  Google Scholar 

  • Finelli A, Kelkar A, Song HJ, Yang H and Konsolaki M (2004) A model for studying Alzheimer's Abeta42-induced toxicity in Drosophila melanogaster. Mol Cell Neurosci 26: 365–375

    Article  CAS  PubMed  Google Scholar 

  • Foster NL, Wilhelmsen K, Sima AA, Jones MZ, D'Amato CJ and Gilman S (1997) Frontotemporal dementia and Parkinsonism linked to chromosome 17: A consensus conference. Conference Participants. Ann Neurol 41: 706–715

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Goedert M, Spillantini MG, Cairns NJ and Crowther RA (1992) Tau proteins of Alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms. Neuron 8: 159–168

    Article  CAS  PubMed  Google Scholar 

  • Gotz J, Chen F, van Dorpe J and Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293: 1491–1495

    Article  CAS  PubMed  Google Scholar 

  • Greenberg SG and Davies P (1990) A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc Natl Acad Sci USA 87: 5827–5831

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Greeve I, Kretzschmar D, Tschape JA, Beyn A, Brellinger C and Schweizer M et al. (2004) Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila. J Neurosci 24: 3899–3906

    Article  CAS  PubMed  Google Scholar 

  • Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM and Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83: 4913–4917

    CAS  PubMed  Google Scholar 

  • Guo S and Kemphues KJ (1995) par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell 81: 611–620

    Article  CAS  PubMed  Google Scholar 

  • >Gusella JF and MacDonald ME (2000) Molecular genetics: Unmasking polyglutamine triggers in neurodegenerative disease. Nat Rev Neurosci 1: 109–115

    Article  CAS  PubMed  Google Scholar 

  • Haass C and De Strooper B (1999) The presenilins in Alzheimer's disease-proteolysis holds the key. Science 286: 916–919

    Article  CAS  PubMed  Google Scholar 

  • Hanger DP, Betts JC, Loviny TL, Blackstock WP and Anderton BH (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

    CAS  PubMed  Google Scholar 

  • Hardy J and Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science 297: 353–356

    Article  CAS  PubMed  Google Scholar 

  • Haywood AF and Staveley BE (2004) Parkin counteracts symptoms in a Drosophila model of Parkinson's disease. BMC Neurosci 5: 14

    Article  PubMed  Google Scholar 

  • Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A and Michel PP (2003) The role of glial reaction and inflammation in Parkinson's disease. Ann N Y Acad Sci 991: 214–228

    CAS  PubMed  Google Scholar 

  • Hod Y, Pentyala SN, Whyard TC and El-Maghrabi MR (1999) Identification and characterization of a novel protein that regulates RNA–protein interaction. J Cell Biochem 72: 435–444

    Article  CAS  PubMed  Google Scholar 

  • Hou CE, Carlin D and Miller BL (2004) Non-Alzheimer's disease dementias: Anatomic, clinical, and molecular correlates. Can J Psychiatry 49: 164–171

    PubMed  Google Scholar 

  • Houseley JM, Wang Z, Brock GJ, Soloway J, Artero R and Perez-Alonso M et al. (2005) Myotonic dystrophy associated expanded CUG repeat muscleblind positive ribonuclear foci are not toxic to Drosophila. Hum Mol Genet 14: 873–883

    Article  CAS  PubMed  Google Scholar 

  • Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A and Mallory M et al. (2000) Alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol 157: 401–410

    CAS  PubMed  Google Scholar 

  • Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S and 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  CAS  PubMed  Google Scholar 

  • Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolaki M and Zhong Y (2004) Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: A potential model for Alzheimer's disease. Proc Natl Acad Sci USA 101: 6623–6628

    Article  CAS  PubMed  Google Scholar 

  • Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y and Takahashi R (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105: 891–902

    Article  CAS  PubMed  Google Scholar 

  • Ishihara T, Hong M, Zhang B, Nakagawa Y, Lee MK and Trojanowski JQ et al. (1999) Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24: 751–762

    Article  CAS  PubMed  Google Scholar 

  • Jackson GR, Salecker I, Dong X, Yao X, Arnheim N and Faber PW et al. (1998) Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21: 633–642

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Jenner P (2003) Oxidative stress in Parkinson's disease. Ann Neurol 53(Suppl 3): S26–S36; discussion S36–S28

    Article  CAS  PubMed  Google Scholar 

  • Jicha GA, Weaver C, Lane E, Vianna C, Kress Y and Rockwood J et al. (1999) cAMP-dependent protein kinase phosphorylations on tau in Alzheimer's disease. J Neurosci 19: 7486–7494

    CAS  PubMed  Google Scholar 

  • Jin P, Zarnescu DC, Zhang F, Pearson CE, Lucchesi JC and Moses K et al. (2003) RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron 39: 739–747

    Article  CAS  PubMed  Google Scholar 

  • Kazemi-Esfarjani P and Benzer S (2000) Genetic suppression of polyglutamine toxicity in Drosophila. Science 287: 1837–1840

    Article  CAS  PubMed  Google Scholar 

  • Kinumi T, Kimata J, Taira T, Ariga H and Niki E (2004) Cysteine-106 of DJ-1 is the most sensitive cysteine residue to hydrogen peroxide-mediated oxidation in vivo in human umbilical vein endothelial cells. Biochem Biophys Res Commun 317: 722–728

    Article  CAS  PubMed  Google Scholar 

  • Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y and Minoshima S et al. (1998) Mutations in the parkin gene cause autosomal recessive juvenile Parkinsonism. Nature 392: 605–608

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Landis GN, Abdueva D, Skvortsov D, Yang J, Rabin BE and Carrick J et al. (2004) Similar gene expression patterns characterize aging and oxidative stress in Drosophila melanogaster. Proc Natl Acad Sci USA 101: 7663–7668

    Article  CAS  PubMed  Google Scholar 

  • Lee VM, Balin BJ, Otvos L Jr, and Trojanowski JQ (1991) A68: A major subunit of paired helical filaments and derivatized forms of normal Tau. Science 251: 675–678

    CAS  PubMed  Google Scholar 

  • Leroy E, Boyer R, Auburger G, Leube B, Ulm G and Mezey E et al. (1998) The ubiquitin pathway in Parkinson's disease. Nature 395: 451–452

    Article  CAS  PubMed  Google Scholar 

  • Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P and Van Slegtenhorst M et al. (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25: 402–405

    Article  CAS  PubMed  Google Scholar 

  • Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A and Jones G et al. (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293: 1487–1491

    Article  CAS  PubMed  Google Scholar 

  • Lo Bianco C, Schneider BL, Bauer M, Sajadi A, Brice A and Iwatsubo T et al. (2004) Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease. Proc Natl Acad Sci USA 101: 17510–17515

    Article  CAS  PubMed  Google Scholar 

  • Mandelkow EM and Mandelkow E (1998) Tau in Alzheimer's disease. Trends Cell Biol 8: 425–427

    Article  CAS  PubMed  Google Scholar 

  • Mandelkow EM, Drewes G, Biernat J, Gustke N, Van Lint J and Vandenheede JR et al. (1992) Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett 314: 315–321

    Article  CAS  PubMed  Google Scholar 

  • Marsh JL, Walker H, Theisen H, Zhu YZ, Fielder T and Purcell J et al. (2000) Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum Mol Genet 9: 13–25

    Article  CAS  PubMed  Google Scholar 

  • Min KT and Benzer S (1999) Preventing neurodegeneration in the Drosophila mutant bubblegum. Science 284: 1985–1988

    Article  CAS  PubMed  Google Scholar 

  • Mitsumoto A and Nakagawa Y (2001) DJ-1 is an indicator for endogenous reactive oxygen species elicited by endotoxin. Free Radic Res 35: 885–893

    CAS  PubMed  Google Scholar 

  • Mitsumoto A, Nakagawa Y, Takeuchi A, Okawa K, Iwamatsu A and Takanezawa Y (2001) Oxidized forms of peroxiredoxins and DJ-1 on two-dimensional gels increased in response to sublethal levels of paraquat. Free Radic Res 35: 301–310

    CAS  PubMed  Google Scholar 

  • Mudher A, Shepherd D, Newman TA, Mildren P, Jukes JP and Squire A et al. (2004) GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol Psychiatry 9: 522–530

    Article  CAS  PubMed  Google Scholar 

  • Muqit MM and Feany MB (2002) Modelling neurodegenerative diseases in Drosophila: A fruitful approach? Nat Rev Neurosci 3: 237–243

    Article  CAS  PubMed  Google Scholar 

  • Mutsuddi M, Marshall CM, Benzow KA, Koob MD and Rebay I (2004) The spinocerebellar ataxia 8 noncoding RNA causes neurodegeneration and associates with staufen in Drosophila. Curr Biol 14: 302–308

    Article  CAS  PubMed  Google Scholar 

  • Nagai Y, Fujikake N, Ohno K, Higashiyama H, Popiel HA and Rahadian J et al. (2003) Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila. Hum Mol Genet 12: 1253–1259

    Article  CAS  PubMed  Google Scholar 

  • Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K and Iguchi-Ariga SM et al. (1997) DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun 231: 509–513

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE and Kayed R et al. (2003) Triple-transgenic model of Alzheimer's disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron 39: 409–421

    Article  CAS  PubMed  Google Scholar 

  • Oddo S, Billings L, Kesslak JP, Cribbs DH and LaFerla FM (2004) Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43: 321–332

    Article  CAS  PubMed  Google Scholar 

  • Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J and van der Brug M et al. (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44: 595–600

    Article  CAS  PubMed  Google Scholar 

  • Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C and Klose J et al. (2004) Mitochondrial dysfunction and oxidative damage in Parkin-deficient mice. J Biol Chem 279: 18614–18622

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Petrucelli L, O'Farrell C, Lockhart PJ, Baptista M, Kehoe K and Vink L et al. (2002) Parkin protects against the toxicity associated with mutant alpha-synuclein: Proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36: 1007–1019

    Article  CAS  PubMed  Google Scholar 

  • Pollitt SK, Pallos J, Shao J, Desai UA, Ma AA and Thompson LM et al. (2003) A rapid cellular FRET assay of polyglutamine aggregation identifies a novel inhibitor. Neuron 40: 685–694

    Article  CAS  PubMed  Google Scholar 

  • Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A and Dutra A et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276: 2045–2047

    Article  CAS  PubMed  Google Scholar 

  • Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM and Anderson L et al. (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43: 815–825

    Article  CAS  PubMed  Google Scholar 

  • Rissman RA, Poon WW, Blurton-Jones M, Oddo S, Torp R and Vitek MP et al. (2004) Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 114: 121–130

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Sang TK, Li C, Liu W, Rodriguez A, Abrams JM and Zipursky SL et al. (2005) Inactivation of Drosophila Apaf-1 related killer suppresses formation of polyglutamine aggregates and blocks polyglutamine pathogenesis. Hum Mol Genet 14: 357–372

    Article  CAS  PubMed  Google Scholar 

  • Scherzer CR, Jensen RV, Gullans SR and Feany MB (2003) Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson's disease. Hum Mol Genet 12: 2457–2466

    Article  CAS  PubMed  Google Scholar 

  • Shen J and Cookson MR (2004) Mitochondria and dopamine; new insights into recessive Parkinsonism. Neuron 43: 301–304

    Article  CAS  PubMed  Google Scholar 

  • Sherer TB, Betarbet R, Stout AK, Lund S, Baptista M and Panov AV et al. (2002) An in vitro model of Parkinson's disease: Linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. J Neurosci 22: 7006–7015

    CAS  PubMed  Google Scholar 

  • Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A and Schneider R et al. (2001) Ubiquitination of a new form of alpha-synuclein by parkin from human brain: Implications for Parkinson's disease. Science 293: 263–269

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Shulman JM, Benton R and St Johnston D (2000) The Drosophila homolog of C. elegans PAR-1 organizes the oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole. Cell 101: 377–388

    Article  CAS  PubMed  Google Scholar 

  • Singh TJ, Wang JZ, Novak M, Kontzekova E, Grundke-Iqbal I and Iqbal K (1996) Calcium/calmodulin-dependent protein kinase II phosphorylates tau at Ser-262 but only partially inhibits its binding to microtubules. FEBS Lett 387: 145–148

    Article  CAS  PubMed  Google Scholar 

  • Sohal RS (2002) Role of oxidative stress and protein oxidation in the aging process. Free Radic Biol Med 33: 37–44

    Article  CAS  PubMed  Google Scholar 

  • Spillantini MG, Murrell JR, Goedert M, Farlow MR, 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  CAS  PubMed  Google Scholar 

  • Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A and Apostol BL et al. (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413: 739–743

    Article  CAS  PubMed  Google Scholar 

  • Steffan JS, Agrawal N, Pallos J, Rockabrand E, Trotman LC and Slepko N et al. (2004) SUMO modification of Huntingtin and Huntington's disease pathology. Science 304: 100–104

    Article  CAS  PubMed  Google Scholar 

  • Struhl G and Greenwald I (1999) Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398: 522–525

    Article  CAS  PubMed  Google Scholar 

  • Sun TQ, Lu B, Feng JJ, Reinhard C, Jan YN and Fantl WJ et al. (2001) PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling. Nat Cell Biol 3: 628–636

    Article  CAS  PubMed  Google Scholar 

  • Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K and Ariga H (2004) DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep 5: 213–218

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Taira T, Niki T, Seino C, Iguchi-Ariga SM and Ariga H (2001) DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor. J Biol Chem 276: 37556–37563

    Article  CAS  PubMed  Google Scholar 

  • Takahashi-Niki K, Niki T, Taira T, Iguchi-Ariga SM and Ariga H (2004) Reduced anti-oxidative stress activities of DJ-1 mutants found in Parkinson's disease patients. Biochem Biophys Res Commun 320: 389–397

    Article  CAS  PubMed  Google Scholar 

  • Takeyama K, Ito S, Yamamoto A, Tanimoto H, Furutani T and Kanuka H et al. (2002) Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron 35: 855–864

    Article  CAS  PubMed  Google Scholar 

  • Tomancak P, Piano F, Riechmann V, Gunsalus KC, Kemphues KJ and Ephrussi A (2000) A Drosophila melanogaster homologue of Caenorhabditis elegans par-1 acts at an early step in embryonic-axis formation. Nat Cell Biol 2: 458–460

    Article  CAS  PubMed  Google Scholar 

  • Unoki M and Nakamura Y (2001) Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene 20: 4457–4465

    Article  CAS  PubMed  Google Scholar 

  • Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K and Gispert S et al. (2004) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304: 1158–1160

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J and Hutton M et al. (2001) Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293: 711–714

    Article  CAS  PubMed  Google Scholar 

  • Wu YR, Wang CK, Chen CM, Hsu Y, Lin SJ and Lin YY et al. (2004) Analysis of heat-shock protein 70 gene polymorphisms and the risk of Parkinson's disease. Hum Genet 114: 236–241

    Article  CAS  PubMed  Google Scholar 

  • Wyss-Coray T and Mucke L (2002) Inflammation in neurodegenerative disease—A double-edged sword. Neuron 35: 419–432

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Ye Y, Lukinova N and Fortini ME (1999) Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature 398: 525–529

    Article  CAS  PubMed  Google Scholar 

  • Yokota T, Sugawara K, Ito K, Takahashi R, Ariga H and Mizusawa H (2003) Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochem Biophys Res Commun 312: 1342–1348

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Dawson VL and Dawson TM (2000) Oxidative stress and genetics in the pathogenesis of Parkinson's disease. Neurobiol Dis 7: 240–250

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Smith DL, Meriin AB, Engemann S, Russel DE and Roark M et al. (2005) A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. Proc Natl Acad Sci USA 102: 892–897

    Article  CAS  PubMed  Google Scholar 

  • Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M and Lincoln S et al. (2004) Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron 44: 601–607

    Article  CAS  PubMed  Google Scholar 

  • Zou S, Meadows S, Sharp L, Jan LY and Jan YN (2000) Genome-wide study of aging and oxidative stress response in Drosophila melanogaster. Proc Natl Acad Sci USA 97: 13726–13731

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, GRECC, VA Palo Alto Health Care System, Stanford University School of Medicine, Palo Alto, CA, 94304, USA

    Bingwei Lu

Authors
  1. Bingwei Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bingwei Lu.

About this article

Cite this article

Lu, B. Understanding and treating neurodegeneration: insights from the flies. AGE 27, 225–239 (2005). https://doi.org/10.1007/s11357-005-2917-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-005-2917-y

Key words

Search

Navigation