Unraveling the Basis of Neurodegeneration using the Drosophila Eye

  • Pedro Fernandez-FunezEmail author
  • Jonatan Sanchez-Garcia
  • Diego E. Rincon-Limas


Research progress over the last 20 years has identified misfolded proteins and RNAs bearing noncoding repeat expansions as the culprits in most neurodegenerative diseases. This is the diverse group of brain disorders that typically strikes in mid-to-late life causing progressive loss of motor and/or cognitive functions. Pathologically, these diseases are characterized by the aberrant accumulation of protein (amyloids) and RNA (nuclear foci) in brain neurons. It is unclear, though, how these pathogenic assemblies ultimately cause cell death. To fill this gap, these rogue proteins and RNAs have been expressed in transgenic animal models, including the little fly Drosophila melanogaster. In most cases, these neurotoxic agents preserved their intrinsic pathogenicity, resulting in relevant models to understand how they induce neuronal loss. In this regard, the fly eye has become an invaluable research tool because (i) the precise arrangement of its 800 ommatidia facilitates the detection of structural perturbations and (ii) the eye, unlike the brain, is not required for viability. In addition, the unmatched arsenal of genetic tools enables the validation of candidate genes as well as the discovery of unsuspected molecular mechanisms through genetic interactions. Moreover, the recent combination of in silico and in vitro screens followed by validation in the fly eye has provided a wealth of new targets with potential therapeutic application. This chapter describes the Drosophila eye as a powerful tool in the identification of the genetic mechanisms associated with neurodegenerative processes and the discovery of neuroprotective drugs.


Amyotrophic Lateral Sclerosis Ataxia Telangiectasia Mutate Myotonic Dystrophy polyQ Disease polyQ Expansion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank the Bloomington Drosophila Stock Center for strains. We want to apologize for those whose work we could not cite due to space constraints. This work was supported by the NIH grants DP2OD002721 to PF-F and R21NS081356 to DER-L, and star-up funding from the Department of Neurology (UF) to PF-F and DER-L.


  1. 1.
    Agrawal N, Pallos J, Slepko N, Apostol BL, Bodai L et al (2005) Identification of combinatorial drug regimens for treatment of Huntington’s disease using Drosophila. Proc Natl Acad Sci U S A 102:3777–3781PubMedGoogle Scholar
  2. 2.
    Aguzzi A, O’Connor T (2010) Protein aggregation diseases: pathogenicity and therapeutic perspectives. Nat Rev Drug Discov 9:237–248PubMedGoogle Scholar
  3. 3.
    Al-Ramahi I, Lam YC, Chen HK, de Gouyon B, Zhang M et al (2006) CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. J Biol Chem 281:26714–26724PubMedGoogle Scholar
  4. 4.
    Al-Ramahi I, Perez AM, Lim J, Zhang M, Sorensen R et al (2007) dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1. PLoS Genet 3:e234PubMedGoogle Scholar
  5. 5.
    Bayat V, Thiffault I, Jaiswal M, Tetreault M, Donti T et al (2012) Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. PLoS Biol 10:e1001288PubMedGoogle Scholar
  6. 6.
    Bellen HJ, Tong C, Tsuda H (2010) 100 years of Drosophila research and its impact on vertebrate neuroscience: a history lesson for the future. Nat Rev Neurosci 11:514–522PubMedGoogle Scholar
  7. 7.
    Benzer S (1967) Behavioral mutants of Drosophila isolated by countercurrent distribution. Proc Natl Acad Sci U S A 58:1112–1119PubMedGoogle Scholar
  8. 8.
    Bertram L, Hiltunen M, Parkinson M, Ingelsson M, Lange C et al (2005) Family-based association between Alzheimer’s disease and variants in UBQLN1. N Engl J Med 352:884–894PubMedGoogle Scholar
  9. 9.
    Bilen J, Liu N, Burnett BG, Pittman RN, Bonini NM (2006) MicroRNA pathways modulate polyglutamine-induced neurodegeneration. Mol Cell 24:157–163PubMedGoogle Scholar
  10. 10.
    Bilen J, Bonini NM (2007) Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila. PLoS Genet 3:1950–1964PubMedGoogle Scholar
  11. 11.
    Blard O, Feuillette S, Bou J, Chaumette B, Frebourg T et al (2007) Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila. Hum Mol Genet 16:555–566PubMedGoogle Scholar
  12. 12.
    Bortvedt SF, McLear JA, Messer A, Ahern-Rindell AJ, Wolfgang WJ (2010) Cystamine and intrabody co-treatment confers additional benefits in a fly model of Huntington’s disease. Neurobiol Dis 40:130–134PubMedGoogle Scholar
  13. 13.
    Branco J, Al-Ramahi I, Ukani L, Perez AM, Fernandez-Funez P et al (2008) Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases. Hum Mol Genet 17:376–390PubMedGoogle Scholar
  14. 14.
    Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118:401–415PubMedGoogle Scholar
  15. 15.
    Buff H, Smith AC, Korey CA (2007) Genetic modifiers of Drosophila palmitoyl-protein thioesterase 1-induced degeneration. Genetics 176:209–220PubMedGoogle Scholar
  16. 16.
    Cao W, Song HJ, Gangi T, Kelkar A, Antani I et al (2008) Identification of novel genes that modify phenotypes induced by Alzheimer’s beta-amyloid overexpression in Drosophila. Genetics 178:1457–1471PubMedGoogle Scholar
  17. 17.
    Casas-Tinto S, Zhang Y, Sanchez-Garcia J, Gomez-Velazquez M, Rincon-Limas DE et al (2011) The ER stress factor XBP1s prevents amyloid-beta neurotoxicity. Hum Mol Genet 20:2144–2160PubMedGoogle Scholar
  18. 18.
    Chan HY, Warrick JM, Andriola I, Merry D, Bonini NM (2002) Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum Mol Genet 11:2895–2904PubMedGoogle Scholar
  19. 19.
    Charroux B, Freeman M, Kerridge S, Baonza A (2006) Atrophin contributes to the negative regulation of epidermal growth factor receptor signaling in Drosophila. Dev Biol 291:278–290PubMedGoogle Scholar
  20. 20.
    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 18:164–177PubMedGoogle Scholar
  21. 21.
    Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD et al (2003) Interaction of Akt-phosphorylated ataxin-1 with 14–3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113:457–468PubMedGoogle Scholar
  22. 22.
    Chen L, Periquet M, Wang X, Negro A, McLean PJ et al (2009) Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. J Clin Invest 119:3257–3265PubMedGoogle Scholar
  23. 23.
    Chopra V, Fox JH, Lieberman G, Dorsey K, Matson W et al (2007) A small-molecule therapeutic lead for Huntington’s disease: preclinical pharmacology and efficacy of C2–8 in the R6/2 transgenic mouse. Proc Natl Acad Sci U S A 104:16685–16689PubMedGoogle Scholar
  24. 24.
    Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR et al (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166PubMedGoogle Scholar
  25. 25.
    Couthouis J, Hart MP, Erion R, King OD, Diaz Z et al (2012) Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum Mol Genet 21:2899–2911PubMedGoogle Scholar
  26. 26.
    Crowther DC, Kinghorn KJ, Miranda E, Page R, Curry JA et al (2005) Intraneuronal Abeta, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer’s disease. Neuroscience 132:123–135PubMedGoogle Scholar
  27. 27.
    Haro M de, Al-Ramahi I, De Gouyon B, Ukani L, Rosa A et al (2006) MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1. Hum Mol Genet 15:2138–2145PubMedGoogle Scholar
  28. 28.
    Dermaut B, Norga KK, Kania A, Verstreken P, Pan H et al (2005) Aberrant lysosomal carbohydrate storage accompanies endocytic defects and neurodegeneration in Drosophila benchwarmer. J Cell Biol 170:127–139PubMedGoogle Scholar
  29. 29.
    Fanto M, Clayton L, Meredith J, Hardiman K, Charroux B et al (2003) The tumor-suppressor and cell adhesion molecule Fat controls planar polarity via physical interactions with Atrophin, a transcriptional co-repressor. Development 130:763–774PubMedGoogle Scholar
  30. 30.
    Feany MB, Bender WW (2000) A Drosophila model of Parkinson’s disease. Nature 404:394–398PubMedGoogle Scholar
  31. 31.
    Fernandez-Funez P, Nino-Rosales ML, de Gouyon B, She WC, Luchak JM et al (2000) Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408:101–106PubMedGoogle Scholar
  32. 32.
    Fernandez-Funez P, Casas-Tinto S, Zhang Y, Gomez-Velazquez M, Morales-Garza MA et al (2009) In vivo generation of neurotoxic prion protein: role for hsp70 in accumulation of misfolded isoforms. PLoS Genet 5:e1000507PubMedGoogle Scholar
  33. 33.
    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 26:365–375PubMedGoogle Scholar
  34. 34.
    Franceschini N (1972) Pupil and pseudopupil in the compound eye of Drosophila. In: Wehner R (ed) Information processing in the visual systems of arthropods. Springer, Berlin, pp 75–82Google Scholar
  35. 35.
    Fujikake N, Nagai Y, Popiel HA, Okamoto Y, Yamaguchi M et al (2008) Heat shock transcription factor 1-activating compounds suppress polyglutamine-induced neurodegeneration through induction of multiple molecular chaperones. J Biol Chem 283:26188–26197PubMedGoogle Scholar
  36. 36.
    Ganguly A, Feldman RM, Guo M (2008) ubiquilin antagonizes presenilin and promotes neurodegeneration in Drosophila. Hum Mol Genet 17:293–302PubMedGoogle Scholar
  37. 37.
    Greeve I, Kretzschmar D, Tschape JA, Beyn A, Brellinger C et al (2004) Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila. J Neurosci 24:3899–3906PubMedGoogle Scholar
  38. 38.
    Gross GG, Feldman RM, Ganguly A, Wang J, Yu H et al (2008) Role of X11 and ubiquilin as in vivo regulators of the amyloid precursor protein in Drosophila. PLoS ONE 3:e2495PubMedGoogle Scholar
  39. 39.
    Gohil VM, Offner N, Walker JA, Sheth SA, Fossale E et al (2011) Meclizine is neuroprotective in models of Huntington’s disease. Hum Mol Genet 20:294–300PubMedGoogle Scholar
  40. 40.
    Guo M, Hong EJ, Fernandes J, Zipursky SL, Hay BA (2003) A reporter for amyloid precursor protein gamma-secretase activity in Drosophila. Hum Mol Genet 12:2669–2678PubMedGoogle Scholar
  41. 41.
    Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C (2009) The genetics of Parkinson’s syndromes: a critical review. Curr Opin Genet Dev 19:254–265PubMedGoogle Scholar
  42. 42.
    Hong YK, Park SH, Lee S, Hwang S, Lee MJ et al (2011) Neuroprotective effect of SuHeXiang Wan in Drosophila models of Alzheimer’s disease. J Ethnopharmacol 134:1028–1032PubMedGoogle Scholar
  43. 43.
    Hua H, Munter L, Harmeier A, Georgiev O, Multhaup G et al (2011) Toxicity of Alzheimer’s disease-associated Abeta peptide is ameliorated in a Drosophila model by tight control of zinc and copper availability. Biol Chem 392:919–926PubMedGoogle Scholar
  44. 44.
    Iijima K, Chiang HC, Hearn SA, Hakker I, Gatt A et al (2008) Abeta42 mutants with different aggregation profiles induce distinct pathologies in Drosophila. PLoS ONE 3:e1703PubMedGoogle Scholar
  45. 45.
    Jackson GR, Salecker I, Dong X, Yao X, Arnheim N et al (1998) Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21:633–642PubMedGoogle Scholar
  46. 46.
    Jackson GR, Wiedau-Pazos M, Sang TK, Wagle N, Brown CA et al (2002) Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34:509–519PubMedGoogle Scholar
  47. 47.
    Jin P, Zarnescu DC, Zhang F, Pearson CE, Lucchesi JC et al (2003) RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron 39:739–747PubMedGoogle Scholar
  48. 48.
    Jung J, Xu K, Lessing D, Bonini NM (2009) Preventing Ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3. Hum Mol Genet 18:4843–4852PubMedGoogle Scholar
  49. 49.
    Kaltenbach LS, Romero E, Becklin RR, Chettier R, Bell R et al (2007) Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet 3:e82PubMedGoogle Scholar
  50. 50.
    Karsten SL, Sang TK, Gehman LT, Chatterjee S, Liu J et al (2006) A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration. Neuron 51:549–560PubMedGoogle Scholar
  51. 51.
    Kazemi-Esfarjani P, Benzer S (2000) Genetic suppression of polyglutamine toxicity in Drosophila. Science 287:1837–1840PubMedGoogle Scholar
  52. 52.
    Khurana V, Lu Y, Steinhilb ML, Oldham S, Shulman JM et al (2006) TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr Biol 16:230–241PubMedGoogle Scholar
  53. 53.
    Korey CA, MacDonald ME (2003) An over-expression system for characterizing Ppt1 function in Drosophila. BMC Neurosci 4:30PubMedGoogle Scholar
  54. 54.
    Kumar JP (2012) Building an ommatidium one cell at a time. Dev Dyn 241:136–149PubMedGoogle Scholar
  55. 55.
    Lam YC, Bowman AB, Jafar-Nejad P, Lim J, Richman R et al (2006) ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127:1335–1347PubMedGoogle Scholar
  56. 56.
    Lawlor KT, O’Keefe LV, Samaraweera SE, van Eyk CL, McLeod CJ et al (2011) Double-stranded RNA is pathogenic in Drosophila models of expanded repeat neurodegenerative diseases. Hum Mol Genet 20:3757–3768PubMedGoogle Scholar
  57. 57.
    Lanson NA Jr, Maltare A, King H, Smith R, Kim JH et al (2011) A Drosophila model of FUS-related neurodegeneration reveals genetic interaction between FUS and TDP-43. Hum Mol Genet 20:2510–2523PubMedGoogle Scholar
  58. 58.
    Lessing D, Bonini NM (2008) Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila. PLoS Biol 6:e29PubMedGoogle Scholar
  59. 59.
    Lessing D, Bonini NM (2009) Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutants. Nat Rev Genet 10:359–370PubMedGoogle Scholar
  60. 60.
    Li A, Xie Z, Dong Y, McKay KM, McKee ML et al (2007) Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes. Hum Mol Genet 16:2626–2639PubMedGoogle Scholar
  61. 61.
    Li LB, Yu Z, Teng X, Bonini NM (2008) RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 453:1107–1111PubMedGoogle Scholar
  62. 62.
    Li M, Huang Y, Ma AA, Lin E, Diamond MI (2009) Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice. Neurobiol Dis 36:413–420PubMedGoogle Scholar
  63. 63.
    Li Y, Ray P, Rao EJ, Shi C, Guo W et al (2010) A Drosophila model for TDP-43 proteinopathy. Proc Natl Acad Sci U S A 107:3169–3174PubMedGoogle Scholar
  64. 64.
    Lim J, Crespo-Barreto J, Jafar-Nejad P, Bowman AB, Richman R et al (2008) Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452:713–718PubMedGoogle Scholar
  65. 65.
    Liu Z, Wang X, Yu Y, Li X, Wang T et al (2008) A Drosophila model for LRRK2-linked parkinsonism. Proc Natl Acad Sci U S A 105:2693–2698PubMedGoogle Scholar
  66. 66.
    Lorenzo DN, Li MG, Mische SE, Armbrust KR, Ranum LP et al (2010) Spectrin mutations that cause spinocerebellar ataxia type 5 impair axonal transport and induce neurodegeneration in Drosophila. J Cell Biol 189:143–158PubMedGoogle Scholar
  67. 67.
    Luthi-Carter R, Taylor DM, Pallos J, Lambert E, Amore A et al (2010) SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci U S A 107:7927–7932PubMedGoogle Scholar
  68. 68.
    Maher P, Dargusch R, Bodai L, Gerard PE, Purcell JM et al (2011) ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington’s disease. Hum Mol Genet 20:261–270PubMedGoogle Scholar
  69. 69.
    Marsh JL, Walker H, Theisen H, Zhu YZ, Fielder T et al (2000) Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum Mol Genet 9:13–25PubMedGoogle Scholar
  70. 70.
    Mast JD, Tomalty KM, Vogel H, Clandinin TR (2008) Reactive oxygen species act remotely to cause synapse loss in a Drosophila model of developmental mitochondrial encephalopathy. Development 135:2669–2679PubMedGoogle Scholar
  71. 71.
    McConoughey SJ, Basso M, Niatsetskaya ZV, Sleiman SF, Smirnova NA et al (2010) Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease. EMBO Mol Med 2:349–370PubMedGoogle Scholar
  72. 72.
    Miguel L, Frebourg T, Campion D, Lecourtois M (2011) Both cytoplasmic and nuclear accumulations of the protein are neurotoxic in Drosophila models of TDP-43 proteinopathies. Neurobiol Dis 41:398–406PubMedGoogle Scholar
  73. 73.
    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 17:3601–3616PubMedGoogle Scholar
  74. 74.
    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
  75. 75.
    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 116:671–682PubMedGoogle Scholar
  76. 76.
    Nisoli I, Chauvin JP, Napoletano F, Calamita P, Zanin V et al (2010) Neurodegeneration by polyglutamine Atrophin is not rescued by induction of autophagy. Cell Death Differ 17:1577–1587PubMedGoogle Scholar
  77. 77.
    Pallos J, Bodai L, Lukacsovich T, Purcell JM, Steffan JS et al (2008) Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington’s disease. Hum Mol Genet 17:3767–3775PubMedGoogle Scholar
  78. 78.
    Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP et al (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447:859–863PubMedGoogle Scholar
  79. 79.
    Park J, Lee SB, Lee S, Kim Y, Song S et al (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157–1161PubMedGoogle Scholar
  80. 80.
    Phillips SE, Woodruff EA 3rd, Liang P, Patten M, Broadie K (2008) Neuronal loss of Drosophila NPC1a causes cholesterol aggregation and age-progressive neurodegeneration. J Neurosci 28:6569–6582PubMedGoogle Scholar
  81. 81.
    Pollitt SK, Pallos J, Shao J, Desai UA, Ma AA et al (2003) A rapid cellular FRET assay of polyglutamine aggregation identifies a novel inhibitor. Neuron 40:685–694PubMedGoogle Scholar
  82. 82.
    Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ et al (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A 105:1638–1643PubMedGoogle Scholar
  83. 83.
    Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S et al (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–595PubMedGoogle Scholar
  84. 84.
    Ren J, Jegga AG, Zhang M, Deng J, Liu J et al (2011) A Drosophila model of the neurodegenerative disease SCA17 reveals a role of RBP-J/Su(H) in modulating the pathological outcome. Hum Mol Genet 20:3424–3436PubMedGoogle Scholar
  85. 85.
    Rimkus SA, Katzenberger RJ, Trinh AT, Dodson GE, Tibbetts RS et al (2008) Mutations in String/CDC25 inhibit cell cycle re-entry and neurodegeneration in a Drosophila model of Ataxia telangiectasia. Genes Dev 22:1205–1220PubMedGoogle Scholar
  86. 86.
    Rincon-Limas D, Jensen K, Fernandez Funez A (2012) Drosophila models of proteinopathies: the little fly that could. Curr Pharm Des 18:1108–1122PubMedGoogle Scholar
  87. 87.
    Ross CA, Tabrizi SJ (2011) Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 10:83–98PubMedGoogle Scholar
  88. 88.
    Romero E, Cha GH, Verstreken P, Ly CV, Hughes RE et al (2008) Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm. Neuron 57:27–40PubMedGoogle Scholar
  89. 89.
    Sang TK, Li C, Liu W, Rodriguez A, Abrams JM et al (2005) Inactivation of Drosophila Apaf-1 related killer suppresses formation of polyglutamine aggregates and blocks polyglutamine pathogenesis. Hum Mol Genet 14:357–372PubMedGoogle Scholar
  90. 90.
    Sarkar S, Krishna G, Imarisio S, Saiki S, O’Kane CJ et al (2008) A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum Mol Genet 17:170–178PubMedGoogle Scholar
  91. 91.
    Shieh SY, Bonini NM (2011) Genes and pathways affected by CAG-repeat RNA-based toxicity in Drosophila. Hum Mol Genet 20:4810–4821PubMedGoogle Scholar
  92. 92.
    Shulman JM, Feany MB (2003) Genetic modifiers of tauopathy in Drosophila. Genetics 165:1233–1242PubMedGoogle Scholar
  93. 93.
    Shulman JM, Chipendo P, Chibnik LB, Aubin C, Tran D et al (2011) Functional screening of Alzheimer pathology genome-wide association signals in Drosophila. Am J Hum Genet 88:232–238PubMedGoogle Scholar
  94. 94.
    Sofola OA, Jin P, Qin Y, Duan R, Liu H et al (2007a) RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron 55:565–571Google Scholar
  95. 95.
    Sofola OA, Jin P, Botas J, Nelson DL (2007b) Argonaute-2-dependent rescue of a Drosophila model of FXTAS by FRAXE premutation repeat. Hum Mol Genet 16:2326–2332Google Scholar
  96. 96.
    Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A et al (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413:739–743PubMedGoogle Scholar
  97. 97.
    Steffan JS, Agrawal N, Pallos J, Rockabrand E, Trotman LC et al (2004) SUMO modification of Huntingtin and Huntington’s disease pathology. Science 304:100–104PubMedGoogle Scholar
  98. 98.
    Steinhilb ML, Dias-Santagata D, Mulkearns EE, Shulman JM, Biernat J et al (2007) S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila. J Neurosci Res 85:1271–1278PubMedGoogle 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 18:5060–5068PubMedGoogle Scholar
  100. 100.
    Takeyama K, Ito S, Yamamoto A, Tanimoto H, Furutani T et al (2002) Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron 35:855–864PubMedGoogle Scholar
  101. 101.
    Tan H, Poidevin M, Li H, Chen D, Jin P (2012) MicroRNA-277 modulates the neurodegeneration caused by Fragile X premutation rCGG repeats. PLoS Genet 8:e1002681PubMedGoogle Scholar
  102. 102.
    Tare M, Modi RM, Nainaparampil JJ, Puli OR, Bedi S et al (2011) Activation of JNK signaling mediates amyloid-ss-dependent cell death. PLoS One 6:e24361PubMedGoogle Scholar
  103. 103.
    Taylor JP, Taye AA, Campbell C, Kazemi-Esfarjani P, Fischbeck KH et al (2003) Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein. Genes Dev 17:1463–1468PubMedGoogle Scholar
  104. 104.
    Todd PK, SY Oh, Krans A, Pandey UB, Di Prospero NA et al (2010) Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome. PLoS Genet 6:e1001240PubMedGoogle Scholar
  105. 105.
    Eyk CL van, O’Keefe LV, Lawlor KT, Samaraweera SE, McLeod CJ et al (2011) Perturbation of the Akt/Gsk3-beta signalling pathway is common to Drosophila expressing expanded untranslated CAG, CUG and AUUCU repeat RNAs. Hum Mol Genet 20:2783–2794PubMedGoogle Scholar
  106. 106.
    Venderova K, Kabbach G, Abdel-Messih E, Zhang Y, Parks RJ et al (2009) Leucine-Rich Repeat Kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson’s disease. Hum Mol Genet 18:4390–4404PubMedGoogle Scholar
  107. 107.
    Venkatachalam K, Long AA, Elsaesser R, Nikolaeva D, Broadie K et al (2008) Motor deficit in a Drosophila model of mucolipidosis type IV due to defective clearance of apoptotic cells. Cell 135:838–851PubMedGoogle Scholar
  108. 108.
    Wang D, Qian L, Xiong H, Liu J, Neckameyer WS et al (2006) Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. Proc Natl Acad Sci U S A 103:13520–13525PubMedGoogle Scholar
  109. 109.
    Warrick JM, Paulson HL, Gray-Board GL, Bui QT, Fischbeck KH et al (1998) Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93:939–949PubMedGoogle Scholar
  110. 110.
    Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL et al (1999) Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 23:425–428PubMedGoogle Scholar
  111. 111.
    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 283:24972–24981PubMedGoogle Scholar
  112. 112.
    Whitworth AJ, Lee JR, Ho VM, Flick R, Chowdhury R et al (2008) Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson’s disease factors Pink1 and Parkin. Dis Model Mech 1: 168–174; discussion 173.Google Scholar
  113. 113.
    Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J et al (2001) Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293:711–714PubMedGoogle Scholar
  114. 114.
    Wolfgang WJ, Miller TW, Webster JM, Huston JS, Thompson LM et al (2005) Suppression of Huntington’s disease pathology in Drosophila by human single-chain Fv antibodies. Proc Natl Acad Sci U S A 102:11563–11568PubMedGoogle Scholar
  115. 115.
    Wu Z, Li C, S Lv, Zhou B (2009) Pantothenate kinase-associated neurodegeneration: insights from a Drosophila model. Hum Mol Genet 18:3659–3672PubMedGoogle Scholar
  116. 116.
    Yang Y, Gehrke S, Haque ME, Imai Y, Kosek J 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 U S A 102:13670–13675PubMedGoogle Scholar
  117. 117.
    Yang Y, Gehrke S, Imai Y, Huang Z, Ouyang 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 U S A 103:10793–10798PubMedGoogle Scholar
  118. 118.
    Yu Z, Teng X, Bonini NM (2011) Triplet repeat-derived siRNAs enhance RNA-mediated toxicity in a Drosophila model for myotonic dystrophy. PLoS Genet 7:e1001340PubMedGoogle Scholar
  119. 119.
    Zhai RG, Zhang F, Hiesinger PR, Cao Y, Haueter CM et al (2008) NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature 452:887–891PubMedGoogle Scholar
  120. 120.
    Zhang S, Xu L, Lee J, Xu T (2002) Drosophila atrophin homolog functions as a transcriptional corepressor in multiple developmental processes. Cell 108:45–56PubMedGoogle Scholar
  121. 121.
    Zhang X, Smith DL, Meriin AB, Engemann S, Russel DE et al (2005) A potent small molecule inhibits polyglutamine aggregation in Huntington’s disease neurons and suppresses neurodegeneration in vivo. Proc Natl Acad Sci U S A 102:892–897PubMedGoogle Scholar
  122. 122.
    Zhang S, Binari R, Zhou R, Perrimon N (2010) A genomewide RNA interference screen for modifiers of aggregates formation by mutant Huntingtin in Drosophila. Genetics 184:1165–1179PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Pedro Fernandez-Funez
    • 1
    • 2
    • 3
    • 4
    Email author
  • Jonatan Sanchez-Garcia
    • 1
  • Diego E. Rincon-Limas
    • 1
    • 3
    • 4
  1. 1.Department of Neurology, McKnight Brain InstituteUniversity of FloridaGainesvilleUSA
  2. 2.Department of NeurosciencesUniversity of FloridaGainesvilleUSA
  3. 3.Department of Neuroscience, Genetics Institute and Center for Translational Research on Neurodegenerative DiseasesUniversity of FloridaGainesvilleUSA
  4. 4.Center for Movement Disorders and NeurorestorationUniversity of FloridaGainesvilleUSA

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