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.

  • Commentary
  • Published:

Is there a cause-and-effect relationship between α-synuclein fibrillization and Parkinson’s disease?

Nature Cell Biology volume 2, pages E115–E119 (2000)Cite this article

Abstract

The first gene to be linked to Parkinson’s disease encodes the neuronal protein α-synuclein. Recent mouse and Drosophila models of Parkinson’s disease support a central role for the process of α-synuclein fibrillization in pathogenesis. However, some evidence indicates that the fibril itself may not be the pathogenic species. Our own biophysical studies suggest that a structured fibrillization intermediate or an alternatively assembled oligomer may be responsible for neuronal death. This speculation can now be experimentally tested in the animal models. Such experiments will have implications for the development of new therapies for Parkinson’s disease and related neurodegenerative diseases.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Images obtained by atomic force microscopy (AFM) of several discrete α-synuclein oligomers; placed in a pathway that is consistent with the time–course of α-synuclein fibrillization and parallels the pathway of Aβ fibrillization, which has been extensively studied25.
Figure 2: A scenario, based on the actual species shown in Fig. 1, that offers one explanation for the imperfect correlation between fibrils/Lewy bodies and Parkinson’s disease.

References

  1. Dunnett, S. B. & Bjorklund, A. Nature Suppl. 399, A32–A39 (1999).

    Article  CAS  Google Scholar 

  2. Dawson, T. M. Cell 101, 115–118 ( 2000).

    Article  CAS  Google Scholar 

  3. Forno, L. S. J. Neuropathol. Exp. Neurol. 55, 259– 272 (1996).

    Article  CAS  Google Scholar 

  4. Kosaka, K. & Iseki, E. Curr. Opin. Neurol. 9, 271–275 (1996).

    Article  CAS  Google Scholar 

  5. Lansbury, P. T. Proc. Natl Acad. Sci. USA 96, 3342– 3344 (1999).

    Article  CAS  Google Scholar 

  6. Lansbury, P. T. Neuron 19, 1151–1154 ( 1997).

    Article  CAS  Google Scholar 

  7. Tanner, C. M. et al. J. Am. Med. Assoc. 281, 341– 346 (1999).

    Article  CAS  Google Scholar 

  8. Polymeropoulos, M. H. et al. Science 276, 2045– 2047 (1997).

    Article  CAS  Google Scholar 

  9. Kruger, R. et al. Nat. Genet. 18, 106–108 (1998).

    Article  CAS  Google Scholar 

  10. Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M. & Goedert, M. Proc. Natl Acad. Sci. USA 95, 6469–6473 (1998).

    Article  CAS  Google Scholar 

  11. Engelender, S. et al. Nat Genet. 22, 110– 114 (1999).

    Article  CAS  Google Scholar 

  12. Baba, M. et al. Am. J. Pathol. 152, 879– 884 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Iwai, A. et al. Neuron 14, 467–475 (1995).

    Article  CAS  Google Scholar 

  14. Weinreb, P. H., Zhen, W., Poon, A. W., Conway, K. A. & Lansbury, P. T. Jr. Biochemistry 35, 13709–13715 (1996).

    Article  CAS  Google Scholar 

  15. Conway, K. A., Harper, J. D. & Lansbury, P. T. Nat. Med. 4, 1318– 1320 (1998).

    Article  CAS  Google Scholar 

  16. Scheller, R. H. & Barchas, J. D. Science 242, 13–14 (1988).

    Article  CAS  Google Scholar 

  17. Jensen, P. H., Nielsen, M. S., Jakes, R., Dotti, C. G. & Goedert, M. J. Biol. Chem. 273, 26292–26294 (1998).

    Article  CAS  Google Scholar 

  18. George, J. M., Jin, H., Woods, W. S. & Clayton, D. F. Neuron 15, 361–372 (1995).

    Article  CAS  Google Scholar 

  19. Abeliovich, A. et al. Neuron 25, 239–252 (2000).

    Article  CAS  Google Scholar 

  20. Masliah, E. et al. Science 287, 1265– 1269 (2000).

    Article  CAS  Google Scholar 

  21. Feany, M. & Bender, W. Nature 404, 394–398 (2000).

    Article  CAS  Google Scholar 

  22. Rochet, J. C. & Lansbury, P. T. Curr. Opin. Struct. Biol. 10, 60–68 (2000).

    Article  CAS  Google Scholar 

  23. Harper, J. D., Lieber, C. M. & Lansbury, P. T. Chem. Biol. 4, 951– 959 (1997).

    Article  CAS  Google Scholar 

  24. Harper, J. D., Wong, S. S., Lieber, C. M. & Lansbury, P. T. Jr. Chem. Biol. 4, 119– 125 (1997).

    Article  CAS  Google Scholar 

  25. Harper, J. D., Wong, S. S., Lieber, C. M. & Lansbury, P. T. Jr. Biochemistry 38, 8972– 8980 (1999).

    Article  CAS  Google Scholar 

  26. Conway, K. A., Harper, J. D. & Lansbury, P. T. Jr. Biochemistry 39, 2552–2563 (2000).

    Article  CAS  Google Scholar 

  27. Conway, K. A., et al. Proc. Natl Acad. Sci. USA (in the press).

  28. Tompkins, M. M. & Hill, W. D. Brain Res. 775, 24–29 (1997).

    Article  CAS  Google Scholar 

  29. Tompkins, M. M., Basgall, E. J., Zamrini, E. & Hill, W. D. Am. J. Pathol. 150, 119–131 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Forno, L. S. & Langston, J. W. Neurodegeneration 2, 19–24 (1993).

    Google Scholar 

  31. Moechars, D. et al. J. Biol. Chem. 274, 6483– 6492 (1999).

    Article  CAS  Google Scholar 

  32. Hsia, A. Y. et al. Proc. Natl Acad. Sci. USA 96, 3228– 3233 (1999).

    Article  CAS  Google Scholar 

  33. Chiesa, R., Piccardo, P., Ghetti, B. & Harris, D. A. Neuron 21, 1339–1351 (1998).

    Article  CAS  Google Scholar 

  34. Kazemi–Esfarjani, P. & Benzer, S. Science 287, 1837 –1840 (2000).

    Article  Google Scholar 

  35. Leroy, E. et al. Nature 395, 451–452 (1998).

    Article  CAS  Google Scholar 

  36. Kitada, T. et al. Nature 392, 605–608 (1998).

    Article  CAS  Google Scholar 

  37. Minton, A. P. Curr. Opin. Struct. Biol. 10, 34–39 (2000).

  38. Li, S. H. & Li, X. J. Hum. Mol. Genet. 7, 777–782 (1998).

    Article  CAS  Google Scholar 

  39. Scherzinger, E. et al. Proc. Natl Acad. Sci. USA 96, 4604– 4609 (1999).

    Article  CAS  Google Scholar 

  40. Wyttenbach, A. et al. Proc. Natl Acad. Sci. USA 97, 2898– 2903 (2000).

    Article  CAS  Google Scholar 

  41. Klement, I. A. et al. Cell 95, 41–53 (1998).

    Article  CAS  Google Scholar 

  42. Saudou, F., Finkbeiner, S., Devys, D. & Greenberg, M. E. Cell 95, 55–66 ( 1998).

    Article  CAS  Google Scholar 

  43. Cummings, C. J. et al. Neuron 24, 879–892 (1999).

    Article  CAS  Google Scholar 

  44. Cummings, C. J. et al. Nat Genet. 19, 148– 154 (1998).

    Article  CAS  Google Scholar 

  45. Kobayashi, Y. et al. J. Biol. Chem. 275, 8772– 8778 (2000).

    Article  CAS  Google Scholar 

  46. Faber, P. W., Alter, J. R., MacDonald, M. E. & Hart, A. C. Proc. Natl Acad. Sci. USA 96, 179– 184 (1999).

    Article  CAS  Google Scholar 

  47. Yamamoto, A., Lucas, J. J. & Hen, R. Cell 101, 57–66 (2000).

    Article  CAS  Google Scholar 

  48. Chai, Y., Koppenhafer, S. L., Bonini, N. M. & Paulson, H. L. J. Neurosci. 19, 10338–10347 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the NINDS for their support in the form of a Morris K. Udall Parkinson’s disease research center of excellence at Brigham and Women’s Hospital. The continuing support of the Foundation for Neurologic Diseases (Newburyport, Massachusetts) is also gratefully acknowledged. P.L. thanks the Alzheimer’s Association for a 1999 Zenith award. M.S.G. acknowledges the NIH for support in the form of a postdoctoral traineeship in molecular biology of neurodegeneration. We also thank the following individuals for suggestions concerning the manuscript: Mel Feany, Michael Schlossmacher, Matthew Frosch, Jie Shen, Anne Hart, Ethan Signer and members of the Lansbury laboratory. We also thank Parsa Kazemi–Esfarjani and Mel Feany for sharing their unpublished results and Tomas Ding for supplying the AFM images in Fig. 1.

Author information

Authors and Affiliations

  1. the Center for Neurologic Diseases, Brigham

    Matthew S. Goldberg & Peter T. Lansbury Jr

  2. Women’s Hospital, Harvard Medical School, The Department of Neurology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts, 02115, USA

    Matthew S. Goldberg & Peter T. Lansbury Jr

Authors
  1. Matthew S. Goldberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter T. Lansbury Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter T. Lansbury Jr.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goldberg, M., Lansbury Jr, P. Is there a cause-and-effect relationship between α-synuclein fibrillization and Parkinson’s disease?. Nat Cell Biol 2, E115–E119 (2000). https://doi.org/10.1038/35017124

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35017124

This article is cited by

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