Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A Drosophila model of Parkinson's disease

Nature volume 404, pages 394–398 (2000)Cite this article

Abstract

Parkinson's disease is a common neurodegenerative syndrome characterized by loss of dopaminergic neurons in the substantia nigra, formation of filamentous intraneuronal inclusions (Lewy bodies) and an extrapyramidal movement disorder. Mutations in the α-synuclein gene are linked to familial Parkinson's disease1,2 and α-synuclein accumulates in Lewy bodies and Lewy neurites3,4,5. Here we express normal and mutant forms of α-synuclein in Drosophila and produce adult-onset loss of dopaminergic neurons, filamentous intraneuronal inclusions containing α-synuclein and locomotor dysfunction. Our Drosophila model thus recapitulates the essential features of the human disorder, and makes possible a powerful genetic approach to Parkinson's disease.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Histological and immunocytochemical analysis of α-synuclein transgenic flies.
Figure 2: Electron microscopy of α-synuclein inclusions in flies.
Figure 3: Premature loss of climbing ability in α-synuclein transgenic flies.
Figure 4: Retinal degeneration in α-synuclein transgenic flies.

References

  1. Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045 –2047 (1997).

    Article  CAS  Google Scholar 

  2. Krüger, R. et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nature Genet. 18, 106 –108 (1998).

    Article  Google Scholar 

  3. Spillantini, M. G., Schmidt, M. L., Lee, V. M. -Y. & Trojanowski, J. Q. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997).

    Article  ADS  CAS  Google Scholar 

  4. Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M. & Goedert, M. α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proc. Natl Acad. Sci. USA 95, 6469 –6473 (1998).

    Article  ADS  CAS  Google Scholar 

  5. Baba, M. et al.Aggregation of α-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am. J. Pathol. 152, 879–884 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Brand, A. H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 ( 1993).

    CAS  Google Scholar 

  7. Warrick, J. M. et al. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93, 939–949 (1998).

    Article  CAS  Google Scholar 

  8. Budnik, V., Martin-Morris, L. & White, K. Perturbed pattern of catecholamine-containing neurons in mutant Drosophila deficient in the enzyme dopa decarboxylase. J. Neurosci. 6, 3682–3691 (1986).

    Article  CAS  Google Scholar 

  9. Budnik, V. & White, L. Catecholamine-containing neurons in Drosophila melanogaster: Distribution and development. J. Comp. Neurol. 268, 400–413 ( 1988).

    Article  CAS  Google Scholar 

  10. Lundell, M. J. & Hirsh, J. Temporal and spatial development of serotonin and dopamine neurons in the Drosophila CNS. Dev. Biol. 165, 385–396 (1994).

    Article  CAS  Google Scholar 

  11. Gibbs, W. R. G. & Lees, A. J. Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 54, 388–396 ( 1991).

    Article  Google Scholar 

  12. Coombe, P. E. & Heisenberg, M. The structural brain mutant Vacuolar medulla of Drosophila melanogaster with specific behavioral defects and cell degeneration in the adult. J. Neurogenet. 3, 135–158 (1986).

    Article  CAS  Google Scholar 

  13. Buchanan, R. L. & Benzer, S. Defective glia in the Drosophila brain degeneration mutant drop-dead. Neuron 10, 839–850 ( 1993).

    Article  CAS  Google Scholar 

  14. Jellinger, K. A. Pathology of Parkinson's disease. Changes other than the nigrostriatal pathway. Mol. Chem. Neuropathol. 14, 153– 197 (1991).

    Article  CAS  Google Scholar 

  15. Vallés, A. M. & White, K. Serotonin-containing neurons in Drosophila melanogaster: Development and distribution. J. Comp. Neurol. 268, 414–428 (1988).

    Article  Google Scholar 

  16. Kuzuhara, S., Mori, H., Izumiyama, N., Yoshimura, M. & Ihara, Y. Lewy bodies are ubiquitinated: a light and electron microscopic immunocytochemical study. Acta Neuropathol. 75, 345–353 (1988).

    Article  CAS  Google Scholar 

  17. Dickson, D. W. et al. Diffuse Lewy body disease: light and electron microscopic immunocytochemistry of senile plaques. Acta Neuropathol. 78, 572–584 (1987).

    Article  Google Scholar 

  18. Pollanen, M. S., Dickson, D. W. & Bergeron, C. Pathology and biology of the Lewy body. J. Neuropathol. Exp. Neurol. 52, 183– 191 (1993).

    Article  CAS  Google Scholar 

  19. Ganetzky, B. & Flanagan, J. R. On the relationship between senescence and age-related changes in two wild-type strains of Drosophila melanogaster. Exp. Gerontol. 13, 189 –196 (1978).

    Article  CAS  Google Scholar 

  20. Le Bourg, E. & Lints, F. A. Hypergravity and aging in Drosophila melanogaster. 4. Climbing activity. Gerontology 38, 59–64 (1992).

    Article  CAS  Google Scholar 

  21. Franceschini, N. in Information Processing in the Visual System of Drosophila (ed. Wehner, R.) 75–82 (Springer, Berlin, 1972).

    Google Scholar 

  22. Conway, K. A., Harper, J. D. & Lansbury, P. T. Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease. Nature Med. 4, 1318–1320 (1998).

    Article  CAS  Google Scholar 

  23. Narhi, L. et al. Both familial Parkinson's disease mutations accelerate α-synuclein aggregation. J. Biol. Chem. 274, 9843– 9846 (1999).

    Article  CAS  Google Scholar 

  24. El-Agnaf, O. M. A. et al. Aggregates from mutant and wild-type α-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of β-sheet and amyloid-like filaments. FEBS Lett. 440, 71–75 ( 1998).

    Article  CAS  Google Scholar 

  25. Ostreova, N. et al. α-synuclein shares physical and functional homology with 14-3-3 proteins. J. Neurosci. 19, 5782–5791 (1999).

    Article  Google Scholar 

  26. Hong, L. et al. The cDNA cloning and ontogeny of mouse α-synuclein. NeuroReport 9, 1239–1243 (1998).

    Article  CAS  Google Scholar 

  27. Masliah, E. et al. Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 287, 1265–1269 (2000).

    Article  ADS  CAS  Google Scholar 

  28. Li, H., Chaney, S., Forte, M. & Hirsh, J. Ectopic G-protein expression in dopamine and serotonin neurons blocks cocaine sensitization in Drosophila melanogaster. Curr. Biol. (in the press).

  29. Robinow, S. & White, L. The locus elav of Drosophila melanogaster is expressed in all neurons at all developmental stages. Dev. Biol. 126, 294–303 (1988).

    Article  CAS  Google Scholar 

  30. Ellis M., O'Neill, E. & Rubin, G. Expression of Drosophila glass protein and evidence for negative regulation of its activity in non-neuronal cells by another DNA-binding protein. Development 119, 855–865 (1993).

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank J. Hirsh, J. Hardy, M. Farrer and H. Orr for flies and DNAs; J. Hirsh, D. Dickson, M. Frosch, K. Buckley, W. Quinn and D. Morisato for discussions; and H. Shing, L. Trakimas, A. Merola, C. Ridolfi and M. Ericsson for technical assistance. M.B.F. thanks J. Gusella and the American Parkinson Disease Foundation for encouragement. Support was provided by a Howard Hughes Physician Postdoctoral Fellowship and a grant from the N.I.A. to M.B.F, and by a grant from the N.I.H. to W.B.

Author information

Authors and Affiliations

  1. Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Harvard Medical School and,

    Mel B. Feany

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, 02115, Massachusetts , USA

    Welcome W. Bender

Authors
  1. Mel B. Feany
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Welcome W. Bender
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mel B. Feany.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Feany, M., Bender, W. A Drosophila model of Parkinson's disease. Nature 404, 394–398 (2000). https://doi.org/10.1038/35006074

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35006074

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing