From fruit fly to bedside: Translating lessons from Drosophila models of neurodegenerative disease

Current Opinion in Neurology

Volumn 16, Issue 4, 2003, Pages 443-449

  Shulman, Joshua M ^a   Shulman, Lisa M ^b   Weiner, William J ^b   Feany, Mel B ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

Author keywords

Alzheimer's disease; Animal models; Drosophila melanogaster; Drug design; Huntington's disease; Neurodegenerative diseases; Parkinson's disease; Polyglutamine repeat; Spinocerebellar ataxia; Tauopathy; Translational research

Indexed keywords

PHOSPHOTRANSFERASE; POLYGLUTAMINE;

ALZHEIMER DISEASE; ANIMAL EXPERIMENT; ANIMAL MODEL; APOPTOSIS; DEGENERATIVE DISEASE; DROSOPHILA MELANOGASTER; DRUG DESIGN; GENETIC CONSERVATION; GENETICS; HUNTINGTON CHOREA; MEDICAL RESEARCH; NONHUMAN; PARKINSON DISEASE; PATHOGENESIS; PROTEIN DEGRADATION; PROTEIN FOLDING; REVIEW; RNA TRANSLATION; SPINOCEREBELLAR DEGENERATION; TAUOPATHY; TRANSGENE;

AMYLOID BETA-PROTEIN PRECURSOR; ANIMALS; DISEASE MODELS, ANIMAL; DROSOPHILA; HEAT-SHOCK PROTEINS; HSP40 HEAT-SHOCK PROTEINS; HSP70 HEAT-SHOCK PROTEINS; HUMANS; NERVE TISSUE PROTEINS; NEURODEGENERATIVE DISEASES; NUCLEAR PROTEINS; PEPTIDES; SYNUCLEINS; TRANSGENES;

EID: 0042627722     PISSN: 13507540     EISSN: None     Source Type: Journal    
DOI: 10.1097/00019052-200308000-00001     Document Type: Review

References (39)

1. Muqit MMK, Feany MB. Modelling neurodegenerative diseases in Drosophila: a fruitful approach? Nat Rev Neurosci 2002; 3:237-243.
2. Zoghbi HY, Botas J. Mouse and fly models of neurodegeneration. Trends Genet 2002; 18:463-471.
3. Fortini ME, Skupski MP, Boguski MS, Hariharan IK. A survey of human disease gene counterparts in the Drosophila genome. J Cell Biol 2000; 150:F23-F30.
4. Rubin GM, Yandell MD, Wortman JR, et al. Comparative genomics of the eukaryotes. Science 2000; 287:2204-2215.
5. Struhl G, Greenwald I. Presenilin-mediated transmembrane cleavage is required for notch signal transduction in Drosophila. Proc Natl Acad Sci U S A 2001; 98:229-234.
6. Struhl G, Greenwald I. Presenilin is required for activity and nuclear access of notch in Drosophila. Nature 1999; 398:522-525.
7. Ye Y, Lukinova N, Fortini ME. Neurogenic phenotypes and altered notch processing in Drosophila presenilin mutants. Nature 1999; 398:525-529.
8. Lopez-Schier H, St Johnston D. Drosophila nicastrin is essential for the intramembranous cleavage of notch. Dev Cell 2002; 2:79-89. See Ref. [9•].
9. Hu Y, Ye Y, Fortini ME. Nicastrin is required for gamma-secretase cleavage of the Drosophila notch receptor. Dev Cell 2002; 2:69-78. Refs [9•,10•] identify Drosophila nicastrin, and demonstrate its requirement for presenilin-mediated proteolysis of notch during signal transduction. These results can be generalized to our understanding of presenilin and nicastrin function in the γ-secretase cleavage of amyloid precursor protein to Aβ in Alzheimer's disease.
10. Chung HM, Struhl G. Nicastrin is required for presenilin-mediated transmembrane cleavage in Drosophila. Nat Cell Biol 2001; 3:1129-1132.
11. Luo L, Tully T, White K. Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron 1992; 9:595-605.
12. Gunawardena S, Goldstein LS. Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 2001; 32:389-401.
13. Kamal A, Stokin GB, Yang Z, et al. Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron 2000; 28:449-459.
14. Heidary G, Fortini ME. Identification and characterization of the Drosophila tau homolog. Mech Dev 2001; 108:171-178.
15. Shimura H, Hattori N, Kubo S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 2000; 25:302-305.
16. Greene JC, Whitworth AJ, Kuo I, et al. Drosophila parkin mutants exhibit mitochondrial pathology and apoptotic muscle degeneration. Proc Natl Acad Sci U S A 2003; 100:4078-4083. This important loss of function study supports a role for mitochondrial dysfunction in Parkinson's disease. Drosophila parkin mutants show apoptotic muscle degeneration with concomitant mitochondrial swelling and a truncated lifespan; interestingly however, dopaminergic neurons were spared.
17. Erkner A, Roure A, Charroux B, et al. Grunge, related to human atrophin-like proteins, has multiple functions in Drosophila development. Development 2002; 129:1119-1129.
18. Zhang S, Xu L, Lee I Xu T. Drosophila atrophin homolog functions as a transcriptional corepressor in multiple developmental processes. Cell 2002; 108:45-56.
19. Feany MB, Bender WW. A Drosophila model of Parkinson's disease. Nature 2000; 404:394-398.
20. Wittmann CW, Wszolek MF, Shulman JM, et al. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 2001; 293:711-714.
21. Warrick JM, Paulson HL, Gray-Board GL, et al. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 1998; 93:939-949.
22. Jackson GR, Salecker I, Dong X, et al. Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 1998; 21:633-642.
23. Steffan JS, Bodai L, Pallos J, et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 2001; 413:739-743.
24. Chan HY, Warrick JM, Andriola I, et al. Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum Mol Genet 2002; 11:2895-2904.
25. Takeyama K, Ito S, Yamamoto A, et al. Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron 2002; 35:855-864. This elegant study develops a Drosophila model of spinal and bulbar muscular atrophy that recapitulates both a loss and gain-of-function in the human androgen receptor. The polyglutamine-expanded form of the human androgen receptor is shown to have lost the ability to activate transcription and gained androgen-dependent, neurotoxic properties.
26. Marsh JL, Walker H, Theisen H, et al. Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum Mol Genet 2000; 9:13-25.
27. Kazemi-Esfarjani P, Benzer S. Genetic suppression of polyglutamine toxicity in Drosophila. Science 2000; 287:1837-1840.
28. Jackson GR, Wiedau-Pazos M, Sang TK, et al. Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 2002; 34:509-519. This study demonstrates for the first time that GSK-3β can enhance tau toxicity in vivo. This kinase has long been a candidate drug target for tauopathy given its ability to mediate the pathologic phosphorylations of tau characteristic of neurofibrillary tangles.
29. Fernandez-Funez P, Nino-Rosales ML, de Gouyon B, et al. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 2000; 408:101-106.
30. Warrick JM, Chan HY, Gray-Board GL, et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 1999; 23:425-428.
31. Cummings CJ, Reinstein E, Sun Y, et al. Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 1999; 24:879-892.
32. Cummings CJ, Sun Y, Opal P, et al. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet 2001; 10:1511-1518.
33. Auluck PK, Chan HY, Trojanowski JQ, et al. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 2002; 295:865-868. This important paper extends the findings from a number of Drosophila models of polyglutamine repeat diseases to a Parkinson's disease model, showing that HSP70 can protect dopaminergic neurons from synuclein toxicity.
34. Kazemi-Esfarjani P, Benzer S. Suppression of polyglutamine toxicity by a Drosophila homolog of myeloid leukemia factor 1. Hum Mol Genet 2002; 11:2657-2672. This paper demonstrates how genetic modifier screens using Drosophila models can identify completely unexpected and novel determinants of neurotoxicity. A conserved fly homolog of human myeloid leukemia factor 1 is shown to localize to polyglutamine nuclear-inclusions, suppress retinal toxicity, and extend the life-span of polyglutamine-transgenic flies.
35. Hockly E, Richon VM, Woodman B, et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci U S A 2003; 100:2041-2046. This successful preclinical trial of the histone deacetylase inhibitor, SAHA, in a mouse model of Huntington's disease, follows a similarly successful trial of the compound in a Drosophila model [23].
36. Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med 2001; 344:1688-1700.
37. Lucas JJ, Hernandez F, Gomez-Ramos P, et al. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 2001; 20:27-39.
38. Spittaels K, Van den Haute C, Van Dorpe J, et al. Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J Biol Chem 2000; 275:41340-41349.
39. Kazantsev A, Walker HA, Slepko N, et al. A bivalent huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila. Nat Genet 2002; 30:367-376. This 'preclinical trial' in a Drosophila model of Huntington's disease demonstrates the efficacy of peptides that block aggregation in attenuating polyglutamine toxicity in vivo.