Apoptosis

, Volume 14, Issue 8, pp 1008–1020 | Cite as

Recent advances in using Drosophila to model neurodegenerative diseases

Apoptosis in Drosophila

Abstract

Neurodegenerative diseases are progressive disorders of the nervous system that affect the function and maintenance of specific neuronal populations. Most disease cases are sporadic with no known cause. The identification of genes associated with familial cases of these diseases has enabled the development of animal models to study disease mechanisms. The model organism Drosophila has been successfully used to study pathogenic mechanisms of a wide range of neurodegenerative diseases. Recent genetic studies in the Drosophila models have provided new insights into disease mechanisms, emphasizing the roles played by mitochondrial dynamics, RNA (including miRNA) function, protein translation, and synaptic plasticity and differentiation. It is anticipated that Drosophila models will further our understanding of mechanisms of neurodegeneration and facilitate the development of novel and rational treatments for these debilitating neurodegenerative diseases.

Keywords

Alzheimer’s disease Parkinson’s disease Tauopathies Polyglutamine diseases Prion disease Amyotrophic lateral sclerosis Spinal muscular atrophy Batten disease Mitochondrial dynamics Synaptic dysfunction 

Abbreviations

4E-BP

Eukaryotic initiation factor 4E-binding protein

AD

Alzheimer’s disease

ALS

Amyotrophic lateral sclerosis

APP

Amyloid precursor protein

BACE

β-site APP-cleaving enzyme

CEBP

cAMP-responsive element-binding protein

FMR

Fragile × mental retardation

HD

Huntington’s disease

HDAC

Histone deacetylase

JNCL

Juvenile neuronal ceroid lipofuscinosis

LRRK2

Leucine-rich repeat kinase 2

NFT

Neurofibrillary tangles

NMJ

Neuromuscular junction

Pael-R

Parkin associated endothelin-like receptor

PAR-1

Partioning defective-1

PD

Parkinson’s disease

PINK1

Pten-induced kinase 1

RNAi

RNA interference

SBMA

Spinobulbar muscular strophy

SCA

Spinocerebellar ataxia

SMA

Spinal muscular atrophy

SOD1

Copper, zinc-superoxide dismutase

VAPB

Vesicle-ass ociated membrane protein-associated protein B

SMN

Survival motor neuron

Notes

Acknowledgments

We apologize to those whose work we could not cite because of space constraints. Research in the author’s laboratory is supported by grants from the McKnight Foundation (Brain Disorders Award), Alzheimer’s Association (IIRG0626723), and the NIH (R21NS056878, R01AR054926, R01MH080378, and R01NS043167).

References

  1. 1.
    Bonini NM, Fortini ME (2003) Human neurodegenerative disease modeling using Drosophila. Annu Rev Neurosci 26:627–656. doi:10.1146/annurev.neuro.26.041002.131425 PubMedCrossRefGoogle Scholar
  2. 2.
    Muqit MM, Feany MB (2002) Modelling neurodegenerative diseases in Drosophila: a fruitful approach? Nat Rev Neurosci 3:237–243. doi:10.1038/nrn751 PubMedCrossRefGoogle Scholar
  3. 3.
    Driscoll M, Gerstbrein B (2003) Dying for a cause: invertebrate genetics takes on human neurodegeneration. Nat Rev Genet 4:181–194. doi:10.1038/nrg1018 PubMedCrossRefGoogle Scholar
  4. 4.
    Lu B, Vogel H (2008) Drosophila models of neurodegenerative diseases. Annu Rev Pathol 4:315–342CrossRefGoogle Scholar
  5. 5.
    Rogina B, Benzer S, Helfand SL (1997) Drosophila drop-dead mutations accelerate the time course of age-related markers. Proc Natl Acad Sci USA 94:6303–6306. doi:10.1073/pnas.94.12.6303 PubMedCrossRefGoogle Scholar
  6. 6.
    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 17:7425–7432PubMedGoogle Scholar
  7. 7.
    Akassoglou K, Malester B, Xu J, Tessarollo L, Rosenbluth J, Chao MV (2004) Brain-specific deletion of neuropathy target esterase/swisscheese results in neurodegeneration. Proc Natl Acad Sci USA 101:5075–5080. doi:10.1073/pnas.0401030101 PubMedCrossRefGoogle Scholar
  8. 8.
    Jackson GR, Salecker I, Dong X et al (1998) Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21:633–642. doi:10.1016/S0896-6273(00)80573-5 PubMedCrossRefGoogle Scholar
  9. 9.
    Warrick JM, Paulson HL, Gray-Board GL et al (1998) Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93:939–949. doi:10.1016/S0092-8674(00)81200-3 PubMedCrossRefGoogle Scholar
  10. 10.
    Feany MB, Bender WW (2000) A Drosophila model of Parkinson’s disease. Nature 404:394–398. doi:10.1038/35006074 PubMedCrossRefGoogle Scholar
  11. 11.
    Fernandez-Funez P, Nino-Rosales ML, de Gouyon B et al (2000) Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408:101–106. doi:10.1038/35040584 PubMedCrossRefGoogle Scholar
  12. 12.
    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 100:4078–4083. doi:10.1073/pnas.0737556100 PubMedCrossRefGoogle Scholar
  13. 13.
    Pesah Y, Pham T, Burgess H et al (2004) Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 131:2183–2194. doi:10.1242/dev.01095 PubMedCrossRefGoogle Scholar
  14. 14.
    Yang Y, Nishimura I, Imai Y, Takahashi R, Lu B (2003) Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron 37:911–924. doi:10.1016/S0896-6273(03)00143-0 PubMedCrossRefGoogle Scholar
  15. 15.
    Rong YS, Golic KG (2000) Gene targeting by homologous recombination in Drosophila. Science 288:2013–2018. doi:10.1126/science.288.5473.2013 PubMedCrossRefGoogle Scholar
  16. 16.
    Coulom H, Birman S (2004) Chronic exposure to rotenone models sporadic Parkinson’s disease in Drosophila melanogaster. J Neurosci 24:10993–10998. doi:10.1523/JNEUROSCI.2993-04.2004 PubMedCrossRefGoogle Scholar
  17. 17.
    Chaudhuri A, Bowling K, Funderburk C et al (2007) Interaction of genetic and environmental factors in a Drosophila parkinsonism model. J Neurosci 27:2457–2467. doi:10.1523/JNEUROSCI.4239-06.2007 PubMedCrossRefGoogle Scholar
  18. 18.
    Dexter DT, Sian J, Rose S et al (1994) Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease. Ann Neurol 35:38–44. doi:10.1002/ana.410350107 PubMedCrossRefGoogle Scholar
  19. 19.
    Dunnett SB, Bjorklund A (1999) Prospects for new restorative and neuroprotective treatments in Parkinson’s disease. Nature 399:A32–A39. doi:10.1038/19899 PubMedCrossRefGoogle Scholar
  20. 20.
    Bertoli-Avella AM, Oostra BA, Heutink P (2004) Chasing genes in Alzheimer’s and Parkinson’s disease. Hum Genet 114(5):413–438PubMedCrossRefGoogle Scholar
  21. 21.
    Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822. doi:10.1126/science.1087753 PubMedCrossRefGoogle Scholar
  22. 22.
    Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047. doi:10.1126/science.276.5321.2045 PubMedCrossRefGoogle Scholar
  23. 23.
    Kitada T, Asakawa S, Hattori N et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608. doi:10.1038/33416 PubMedCrossRefGoogle Scholar
  24. 24.
    Leroy E, Boyer R, Auburger G et al (1998) The ubiquitin pathway in Parkinson’s disease. Nature 395:451–452. doi:10.1038/26652 PubMedCrossRefGoogle Scholar
  25. 25.
    Bonifati V, Rizzu P, Squitieri F et al (2003) DJ-1 (PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol Sci 24:159–160. doi:10.1007/s10072-003-0108-0 PubMedCrossRefGoogle Scholar
  26. 26.
    Valente EM, Abou-Sleiman PM, Caputo V et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160. doi:10.1126/science.1096284 PubMedCrossRefGoogle Scholar
  27. 27.
    Zimprich A, Biskup S, Leitner P et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607. doi:10.1016/j.neuron.2004.11.005 PubMedCrossRefGoogle Scholar
  28. 28.
    Paisan-Ruiz C, Jain S, Evans EW et al (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44:595–600. doi:10.1016/j.neuron.2004.10.023 PubMedCrossRefGoogle Scholar
  29. 29.
    Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295:865–868. doi:10.1126/science.1067389 PubMedCrossRefGoogle Scholar
  30. 30.
    Singleton AB, Farrer M, Johnson J et al (2003) Alpha-synuclein locus triplication causes Parkinson’s disease. Science 302:841. doi:10.1126/science.1090278 PubMedCrossRefGoogle Scholar
  31. 31.
    Wu YR, Wang CK, Chen CM et al (2004) Analysis of heat-shock protein 70 gene polymorphisms and the risk of Parkinson’s disease. Hum Genet 114:236–241. doi:10.1007/s00439-003-1050-1 PubMedCrossRefGoogle Scholar
  32. 32.
    Dong Z, Wolfer DP, Lipp HP, 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. doi:10.1016/j.ymthe.2004.09.007 PubMedCrossRefGoogle Scholar
  33. 33.
    Fujiwara H, Hasegawa M, Dohmae N et al (2002) Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164. doi:10.1038/ncb841 PubMedCrossRefGoogle Scholar
  34. 34.
    Chen L, Feany MB (2005) Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 8:657–663. doi:10.1038/nn1443 PubMedCrossRefGoogle Scholar
  35. 35.
    Periquet M, Fulga T, Myllykangas L, Schlossmacher MG, Feany MB (2007) Aggregated alpha-synuclein mediates dopaminergic neurotoxicity in vivo. J Neurosci 27:3338–3346. doi:10.1523/JNEUROSCI.0285-07.2007 PubMedCrossRefGoogle Scholar
  36. 36.
    Outeiro TF, Kontopoulos E, Altmann SM et al (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317:516–519. doi:10.1126/science.1143780 PubMedCrossRefGoogle Scholar
  37. 37.
    Botella JA, Bayersdorfer F, Schneuwly S (2008) Superoxide dismutase overexpression protects dopaminergic neurons in a Drosophila model of Parkinson’s disease. Neurobiol Dis 30:65–73. doi:10.1016/j.nbd.2007.11.013 PubMedCrossRefGoogle Scholar
  38. 38.
    Cooper AA, Gitler AD, Cashikar A et al (2006) Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 313:324–328. doi:10.1126/science.1129462 PubMedCrossRefGoogle Scholar
  39. 39.
    Scherzer CR, Jensen RV, Gullans SR, Feany MB (2003) Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson’s disease. Hum Mol Genet 12:2457–2466. doi:10.1093/hmg/ddg265 PubMedCrossRefGoogle Scholar
  40. 40.
    Xun Z, Sowell RA, Kaufman TC, Clemmer DE (2008) Quantitative proteomics of a presymptomatic A53T alpha-synuclein Drosophila model of Parkinson disease. Mol Cell Proteomics 7:1191–1203. doi:10.1074/mcp.M700467-MCP200 PubMedCrossRefGoogle Scholar
  41. 41.
    Cha GH, Kim S, Park J et al (2005) Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila. Proc Natl Acad Sci USA 102:10345–10350. doi:10.1073/pnas.0500346102 PubMedCrossRefGoogle Scholar
  42. 42.
    Whitworth AJ, Theodore DA, Greene JC, Benes H, Wes PD, Pallanck LJ (2005) Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson’s disease. Proc Natl Acad Sci USA 102:8024–8029. doi:10.1073/pnas.0501078102 PubMedCrossRefGoogle Scholar
  43. 43.
    Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105:891–902. doi:10.1016/S0092-8674(01)00407-X PubMedCrossRefGoogle Scholar
  44. 44.
    Kitao Y, Imai Y, Ozawa K et al (2007) Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation. Hum Mol Genet 16:50–60. doi:10.1093/hmg/ddl439 PubMedCrossRefGoogle Scholar
  45. 45.
    Sang TK, Chang HY, Lawless GM et al (2007) A Drosophila model of mutant human parkin-induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine. J Neurosci 27:981–992. doi:10.1523/JNEUROSCI.4810-06.2007 PubMedCrossRefGoogle Scholar
  46. 46.
    Wang C, Lu R, Ouyang X et al (2007) Drosophila overexpressing parkin R275 W mutant exhibits dopaminergic neuron degeneration and mitochondrial abnormalities. J Neurosci 27:8563–8570. doi:10.1523/JNEUROSCI.0218-07.2007 PubMedCrossRefGoogle Scholar
  47. 47.
    Clark IE, Dodson MW, Jiang C et al (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166. doi:10.1038/nature04779 PubMedCrossRefGoogle Scholar
  48. 48.
    Park J, Lee SB, Lee S et al (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157–1161. doi:10.1038/nature04788 PubMedCrossRefGoogle Scholar
  49. 49.
    Yang Y, Gehrke S, Imai Y et al (2006) Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci USA 103:10793–10798. doi:10.1073/pnas.0602493103 PubMedCrossRefGoogle Scholar
  50. 50.
    Wang D, Qian L, Xiong H et al (2006) Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. Proc Natl Acad Sci USA 103:13520–13525. doi:10.1073/pnas.0604661103 PubMedCrossRefGoogle Scholar
  51. 51.
    Kim Y, Park J, Kim S et al (2008) PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun 377:975–980. doi:10.1016/j.bbrc.2008.10.104 PubMedCrossRefGoogle Scholar
  52. 52.
    Yang Y, Ouyang Y, Yang L et al (2008) Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci USA 105:7070–7075. doi:10.1073/pnas.0711845105 PubMedCrossRefGoogle Scholar
  53. 53.
    Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA 105:1638–1643. doi:10.1073/pnas.0709336105 PubMedCrossRefGoogle Scholar
  54. 54.
    Deng H, Dodson MW, Huang H, Guo M (2008) The Parkinson’s disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci USA 105:14503–14508. doi:10.1073/pnas.0803998105 PubMedCrossRefGoogle Scholar
  55. 55.
    Park J, Lee G, Chung J (2009) The PINK1-Parkin pathway is involved in the regulation of mitochondrial remodeling process. Biochem Biophys Res Commun 378:518–523. doi:10.1016/j.bbrc.2008.11.086 PubMedCrossRefGoogle Scholar
  56. 56.
    Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125:1241–1252. doi:10.1016/j.cell.2006.06.010 PubMedCrossRefGoogle Scholar
  57. 57.
    Li Z, Okamoto K, Hayashi Y, Sheng M (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119:873–887. doi:10.1016/j.cell.2004.11.003 PubMedCrossRefGoogle Scholar
  58. 58.
    Bossy-Wetzel E, Barsoum MJ, Godzik A, Schwarzenbacher R, Lipton SA (2003) Mitochondrial fission in apoptosis, neurodegeneration and aging. Curr Opin Cell Biol 15:706–716. doi:10.1016/j.ceb.2003.10.015 PubMedCrossRefGoogle Scholar
  59. 59.
    Petrucelli L, O’Farrell C, Lockhart PJ et al (2002) Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36:1007–1019. doi:10.1016/S0896-6273(02)01125-X PubMedCrossRefGoogle Scholar
  60. 60.
    Sacktor B (1976) Biochemical adaptations for flight in the insect. Biochem Soc Symp 41:111–131PubMedGoogle Scholar
  61. 61.
    Park SS, Schulz EM, Lee D (2007) Disruption of dopamine homeostasis underlies selective neurodegeneration mediated by alpha-synuclein. Eur J Neurosci 26:3104–3112. doi:10.1111/j.1460-9568.2007.05929.x PubMedCrossRefGoogle Scholar
  62. 62.
    Meulener M, Whitworth AJ, Armstrong-Gold CE et al (2005) Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson’s disease. Curr Biol 15:1572–1577. doi:10.1016/j.cub.2005.07.064 PubMedCrossRefGoogle Scholar
  63. 63.
    Menzies FM, Yenisetti SC, Min KT (2005) Roles of Drosophila DJ-1 in survival of dopaminergic neurons and oxidative stress. Curr Biol 15:1578–1582. doi:10.1016/j.cub.2005.07.036 PubMedCrossRefGoogle Scholar
  64. 64.
    Yang Y, Gehrke S, Haque ME et al (2005) Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proc Natl Acad Sci USA 102:13670–13675. doi:10.1073/pnas.0504610102 PubMedCrossRefGoogle Scholar
  65. 65.
    Kim RH, Peters M, Jang Y et al (2005) DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7:263–273. doi:10.1016/j.ccr.2005.02.010 PubMedCrossRefGoogle Scholar
  66. 66.
    van der Brug MP, Blackinton J, Chandran J et al (2008) RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways. Proc Natl Acad Sci USA 105:10244–10249. doi:10.1073/pnas.0708518105 PubMedCrossRefGoogle Scholar
  67. 67.
    Lee SB, Kim W, Lee S, Chung J (2007) Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila. Biochem Biophys Res Commun 358:534–539. doi:10.1016/j.bbrc.2007.04.156 PubMedCrossRefGoogle Scholar
  68. 68.
    Liu Z, Wang X, Yu Y et al (2008) A Drosophila model for LRRK2-linked parkinsonism. Proc Natl Acad Sci USA 105:2693–2698. doi:10.1073/pnas.0708452105 PubMedCrossRefGoogle Scholar
  69. 69.
    Imai Y, Gehrke S, Wang HQ et al (2008) Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J 27:2432–2443. doi:10.1038/emboj.2008.163 PubMedCrossRefGoogle Scholar
  70. 70.
    De Strooper B (2003) Aph-1, Pen-2, and nicastrin with presenilin generate an active γ-secretase complex. Neuron 38:9–12. doi:10.1016/S0896-6273(03)00205-8 PubMedCrossRefGoogle Scholar
  71. 71.
    Cleveland DW, Hwo SY, Kirschner MW (1977) Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol 116:207–225. doi:10.1016/0022-2836(77)90213-3 PubMedCrossRefGoogle Scholar
  72. 72.
    Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917. doi:10.1073/pnas.83.13.4913 PubMedCrossRefGoogle Scholar
  73. 73.
    Greenberg SG, 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. doi:10.1073/pnas.87.15.5827 PubMedCrossRefGoogle Scholar
  74. 74.
    Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ (1991) A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science 251:675–678. doi:10.1126/science.1899488 PubMedCrossRefGoogle Scholar
  75. 75.
    Foster NL, Wilhelmsen K, Sima AA, Jones MZ, D’Amato CJ, Gilman S (1997) Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference participants. Ann Neurol 41:706–715. doi:10.1002/ana.410410606 PubMedCrossRefGoogle Scholar
  76. 76.
    Hutton M, Lendon CL, Rizzu P et al (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705. doi:10.1038/31508 PubMedCrossRefGoogle Scholar
  77. 77.
    Poorkaj P, Bird TD, Wijsman E et al (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815–825. doi:10.1002/ana.410430617 PubMedCrossRefGoogle Scholar
  78. 78.
    Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 95:7737–7741. doi:10.1073/pnas.95.13.7737 PubMedCrossRefGoogle Scholar
  79. 79.
    Luo L, Tully T, White K (1992) Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron 9:595–605. doi:10.1016/0896-6273(92)90024-8 PubMedCrossRefGoogle Scholar
  80. 80.
    Carmine-Simmen K, Proctor T, Tschape J et al (2008) Neurotoxic effects induced by the Drosophila amyloid-beta peptide suggest a conserved toxic function. Neurobiol Dis 33(2):274–281PubMedCrossRefGoogle Scholar
  81. 81.
    Finelli A, Kelkar A, Song HJ, Yang H, Konsolaki M (2004) A model for studying Alzheimer’s Abeta42-induced toxicity in Drosophila melanogaster. Mol Cell Neurosci 26:365–375. doi:10.1016/j.mcn.2004.03.001 PubMedCrossRefGoogle Scholar
  82. 82.
    Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolaki M, 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. doi:10.1073/pnas.0400895101 PubMedCrossRefGoogle Scholar
  83. 83.
    Stokin GB, Almenar-Queralt A, Gunawardena S et al (2008) Amyloid precursor protein-induced axonopathies are independent of amyloid-beta peptides. Hum Mol Genet 17:3474–3486. doi:10.1093/hmg/ddn240 PubMedCrossRefGoogle Scholar
  84. 84.
    Tan L, Schedl P, Song HJ, Garza D, Konsolaki M (2008) The Toll-->NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer’s Abeta42 polypeptide in Drosophila. PLoS One 3:e3966. doi:10.1371/journal.pone.0003966 PubMedCrossRefGoogle Scholar
  85. 85.
    Iijima-Ando K, Hearn SA, Granger L et al (2008) Overexpression of neprilysin reduces alzheimer amyloid-beta42 (Abeta42)-induced neuron loss and intraneuronal Abeta42 deposits but causes a reduction in cAMP-responsive element-binding protein-mediated transcription, age-dependent axon pathology, and premature death in Drosophila. J Biol Chem 283:19066–19076. doi:10.1074/jbc.M710509200 PubMedCrossRefGoogle Scholar
  86. 86.
    Williams DW, Tyrer M, Shepherd D (2000) Tau and tau reporters disrupt central projections of sensory neurons in Drosophila. J Comp Neurol 428:630–640. doi:10.1002/1096-9861(20001225)428:4≤630::AID-CNE4≥3.0.CO;2-X PubMedCrossRefGoogle Scholar
  87. 87.
    Wittmann CW, Wszolek MF, Shulman JM et al (2001) Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293:711–714. doi:10.1126/science.1062382 PubMedCrossRefGoogle Scholar
  88. 88.
    Jackson GR, Wiedau-Pazos M, Sang TK et al (2002) Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34:509–519. doi:10.1016/S0896-6273(02)00706-7 PubMedCrossRefGoogle Scholar
  89. 89.
    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 11:277–287. doi:10.1101/lm.70804 PubMedCrossRefGoogle Scholar
  90. 90.
    Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159. doi:10.1146/annurev.neuro.24.1.1121 PubMedCrossRefGoogle Scholar
  91. 91.
    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 116:671–682. doi:10.1016/S0092-8674(04)00170-9 PubMedCrossRefGoogle Scholar
  92. 92.
    Guo S, 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. doi:10.1016/0092-8674(95)90082-9 PubMedCrossRefGoogle Scholar
  93. 93.
    Drewes G, Ebneth A, Preuss U, Mandelkow EM, Mandelkow E (1997) MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89:297–308. doi:10.1016/S0092-8674(00)80208-1 PubMedCrossRefGoogle Scholar
  94. 94.
    Bohm H, Brinkmann V, Drab M, Henske A, 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. doi:10.1016/S0960-9822(06)00260-0 PubMedCrossRefGoogle Scholar
  95. 95.
    Biernat J, Wu YZ, Timm T et al (2002) Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity. Mol Biol Cell 13:4013–4028. doi:10.1091/mbc.02-03-0046 PubMedCrossRefGoogle Scholar
  96. 96.
    Shulman JM, Feany MB (2003) Genetic modifiers of tauopathy in Drosophila. Genetics 165:1233–1242PubMedGoogle Scholar
  97. 97.
    Hanger DP, Betts JC, Loviny TL, Blackstock WP, 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 71:2465–2476PubMedCrossRefGoogle Scholar
  98. 98.
    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 18:164–177. doi:10.1093/hmg/ddn326 PubMedCrossRefGoogle Scholar
  99. 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 18:5060–5068. doi:10.1091/mbc.E07-04-0327 PubMedCrossRefGoogle Scholar
  100. 100.
    Karsten SL, Sang TK, Gehman LT et al (2006) A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration. Neuron 51:549–560. doi:10.1016/j.neuron.2006.07.019 PubMedCrossRefGoogle Scholar
  101. 101.
    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 27:574–581. doi:10.1523/JNEUROSCI.5094-06.2007 PubMedCrossRefGoogle Scholar
  102. 102.
    Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791. doi:10.1126/science.1074069 PubMedCrossRefGoogle Scholar
  103. 103.
    Wang P, Yang G, Mosier DR et al (2005) Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. J Neurosci 25:1219–1225. doi:10.1523/JNEUROSCI.4660-04.2005 PubMedCrossRefGoogle Scholar
  104. 104.
    Ashe KH (2000) Synaptic structure and function in transgenic APP mice. Ann N Y Acad Sci 924:39–41PubMedGoogle Scholar
  105. 105.
    Roberson ED, Scearce-Levie K, Palop JJ et al (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754. doi:10.1126/science.1141736 PubMedCrossRefGoogle Scholar
  106. 106.
    Chee FC, Mudher A, Cuttle MF et al (2005) Over-expression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions. Neurobiol Dis 20:918–928. doi:10.1016/j.nbd.2005.05.029 PubMedCrossRefGoogle Scholar
  107. 107.
    Yoshiyama Y, Higuchi M, Zhang B et al (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351. doi:10.1016/j.neuron.2007.01.010 PubMedCrossRefGoogle Scholar
  108. 108.
    Blard O, Feuillette S, Bou J et al (2007) Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila. Hum Mol Genet 16:555–566. doi:10.1093/hmg/ddm011 PubMedCrossRefGoogle Scholar
  109. 109.
    Zhang Y, Guo H, Kwan H, Wang JW, Kosek J, Lu B (2007) par-1 kinase phosphorylates dlg and regulates its postsynaptic targeting at the Drosophila neuromuscular junction. Neuron 53:201–215. doi:10.1016/j.neuron.2006.12.016 PubMedCrossRefGoogle Scholar
  110. 110.
    Almeida CG, Tampellini D, Takahashi RH et al (2005) Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis 20:187–198. doi:10.1016/j.nbd.2005.02.008 PubMedCrossRefGoogle Scholar
  111. 111.
    Gylys KH, Fein JA, Yang F, Wiley DJ, Miller CA, Cole GM (2004) Synaptic changes in Alzheimer’s disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence. Am J Pathol 165:1809–1817PubMedGoogle Scholar
  112. 112.
    Roselli F, Tirard M, Lu J et al (2005) Soluble beta-amyloid1–40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J Neurosci 25:11061–11070. doi:10.1523/JNEUROSCI.3034-05.2005 PubMedCrossRefGoogle Scholar
  113. 113.
    Knight D, Iliadi K, Charlton MP, Atwood HL, Boulianne GL (2007) Presynaptic plasticity and associative learning are impaired in a Drosophila presenilin null mutant. Dev Neurobiol 67:1598–1613. doi:10.1002/dneu.20532 PubMedCrossRefGoogle Scholar
  114. 114.
    Li A, Xie Z, Dong Y, McKay KM, McKee ML, Tanzi RE (2007) Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes. Hum Mol Genet 16:2626–2639. doi:10.1093/hmg/ddm219 PubMedCrossRefGoogle Scholar
  115. 115.
    Gusella JF, MacDonald ME (2000) Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nat Rev Neurosci 1:109–115. doi:10.1038/35039051 PubMedCrossRefGoogle Scholar
  116. 116.
    Kretzschmar D, Tschape J, Bettencourt Da Cruz A et al (2005) Glial and neuronal expression of polyglutamine proteins induce behavioral changes and aggregate formation in Drosophila. Glia 49:59–72. doi:10.1002/glia.20098 PubMedCrossRefGoogle Scholar
  117. 117.
    Lievens JC, Rival T, Iche M, Chneiweiss H, Birman S (2005) Expanded polyglutamine peptides disrupt EGF receptor signaling and glutamate transporter expression in Drosophila. Hum Mol Genet 14:713–724. doi:10.1093/hmg/ddi067 PubMedCrossRefGoogle Scholar
  118. 118.
    Lievens JC, Iche M, Laval M, Faivre-Sarrailh C, Birman S (2008) AKT-sensitive or insensitive pathways of toxicity in glial cells and neurons in Drosophila models of Huntington’s disease. Hum Mol Genet 17:882–894. doi:10.1093/hmg/ddm360 PubMedCrossRefGoogle Scholar
  119. 119.
    Bilen J, Bonini NM (2007) Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila. PLoS Genet 3:1950–1964. doi:10.1371/journal.pgen.0030177 PubMedCrossRefGoogle Scholar
  120. 120.
    Li LB, Yu Z, Teng X, Bonini NM (2008) RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 453:1107–1111. doi:10.1038/nature06909 PubMedCrossRefGoogle Scholar
  121. 121.
    Bilen J, Liu N, Burnett BG, Pittman RN, Bonini NM (2006) MicroRNA pathways modulate polyglutamine-induced neurodegeneration. Mol Cell 24:157–163. doi:10.1016/j.molcel.2006.07.030 PubMedCrossRefGoogle Scholar
  122. 122.
    Chen HK, Fernandez-Funez P, Acevedo SF et al (2003) Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113:457–468. doi:10.1016/S0092-8674(03)00349-0 PubMedCrossRefGoogle Scholar
  123. 123.
    Lim J, Crespo-Barreto J, Jafar-Nejad P et al (2008) Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452:713–718. doi:10.1038/nature06731 PubMedCrossRefGoogle Scholar
  124. 124.
    Lessing D, Bonini NM (2008) Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila. PLoS Biol 6:e29. doi:10.1371/journal.pbio.0060029 PubMedCrossRefGoogle Scholar
  125. 125.
    Al-Ramahi I, Perez AM, Lim J et al (2007) dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1. PLoS Genet 3:e234. doi:10.1371/journal.pgen.0030234 PubMedCrossRefGoogle Scholar
  126. 126.
    Jung J, Bonini N (2007) CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease. Science 315:1857–1859. doi:10.1126/science.1139517 PubMedCrossRefGoogle Scholar
  127. 127.
    Romero E, Cha GH, Verstreken P et al (2008) Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm. Neuron 57:27–40. doi:10.1016/j.neuron.2007.11.025 PubMedCrossRefGoogle Scholar
  128. 128.
    Mugat B, Parmentier ML, Bonneaud N, Chan HY, Maschat F (2008) Protective role of engrailed in a Drosophila model of Huntington’s disease. Hum Mol Genet 17:3601–3616. doi:10.1093/hmg/ddn255 PubMedCrossRefGoogle Scholar
  129. 129.
    Bahadorani S, Hilliker AJ (2008) Antioxidants cannot suppress the lethal phenotype of a Drosophila melanogaster model of Huntington’s disease. Genome 51:392–395. doi:10.1139/G08-012 PubMedCrossRefGoogle Scholar
  130. 130.
    Pallos J, Bodai L, Lukacsovich T et al (2008) Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington’s disease. Hum Mol Genet 17:3767–3775. doi:10.1093/hmg/ddn273 PubMedCrossRefGoogle Scholar
  131. 131.
    Pandey UB, Nie Z, Batlevi Y et al (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447:859–863. doi:10.1038/nature05853 PubMedCrossRefGoogle Scholar
  132. 132.
    Branco J, Al-Ramahi I, Ukani L et al (2008) Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases. Hum Mol Genet 17:376–390. doi:10.1093/hmg/ddm315 PubMedCrossRefGoogle Scholar
  133. 133.
    Latouche M, Lasbleiz C, Martin E et al (2007) A conditional pan-neuronal Drosophila model of spinocerebellar ataxia 7 with a reversible adult phenotype suitable for identifying modifier genes. J Neurosci 27:2483–2492. doi:10.1523/JNEUROSCI.5453-06.2007 PubMedCrossRefGoogle Scholar
  134. 134.
    Jin P, Zarnescu DC, Zhang F et al (2003) RNA-mediated neurodegeneration caused by the fragile × premutation rCGG repeats in Drosophila. Neuron 39:739–747. doi:10.1016/S0896-6273(03)00533-6 PubMedCrossRefGoogle Scholar
  135. 135.
    Jin P, Duan R, Qurashi A et al (2007) Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile × tremor/ataxia syndrome. Neuron 55:556–564. doi:10.1016/j.neuron.2007.07.020 PubMedCrossRefGoogle Scholar
  136. 136.
    Mutsuddi M, Marshall CM, Benzow KA, Koob MD, Rebay I (2004) The spinocerebellar ataxia 8 noncoding RNA causes neurodegeneration and associates with staufen in Drosophila. Curr Biol 14:302–308PubMedGoogle Scholar
  137. 137.
    Gavin BA, Dolph MJ, Deleault NR et al (2006) Accelerated accumulation of misfolded prion protein and spongiform degeneration in a Drosophila model of Gerstmann-Straussler-Scheinker syndrome. J Neurosci 26:12408–12414. doi:10.1523/JNEUROSCI.3372-06.2006 PubMedCrossRefGoogle Scholar
  138. 138.
    Watson MR, Lagow RD, Xu K, Zhang B, Bonini NM (2008) A drosophila model for amyotrophic lateral sclerosis reveals motor neuron damage by human SOD1. J Biol Chem 283:24972–24981. doi:10.1074/jbc.M804817200 PubMedCrossRefGoogle Scholar
  139. 139.
    Ratnaparkhi A, Lawless GM, Schweizer FE, Golshani P, Jackson GR (2008) A Drosophila model of ALS: human ALS-associated mutation in VAP33A suggests a dominant negative mechanism. PLoS One 3:e2334. doi:10.1371/journal.pone.0002334 PubMedCrossRefGoogle Scholar
  140. 140.
    Tsuda H, Han SM, Yang Y et al (2008) The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors. Cell 133:963–977. doi:10.1016/j.cell.2008.04.039 PubMedCrossRefGoogle Scholar
  141. 141.
    Chang HC, Dimlich DN, Yokokura T et al (2008) Modeling spinal muscular atrophy in Drosophila. PLoS One 3:e3209. doi:10.1371/journal.pone.0003209 PubMedCrossRefGoogle Scholar
  142. 142.
    Tuxworth RI, Vivancos V, O’Hare MB, Tear G (2008) Interactions between the juvenile Batten disease gene, CLN3, and the Notch and JNK signalling pathways. Hum Mol Genet 18(4):667–678PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of PathologyStanford University School of MedicineStanfordUSA
  2. 2.GRECCVA Palo Alto Health Care SystemPalo AltoUSA

Personalised recommendations