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Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases

Nature volume 416, pages 507–511 (2002)Cite this article

Abstract

A range of human degenerative conditions, including Alzheimer's disease, light-chain amyloidosis and the spongiform encephalopathies, is associated with the deposition in tissue of proteinaceous aggregates known as amyloid fibrils or plaques. It has been shown previously that fibrillar aggregates that are closely similar to those associated with clinical amyloidoses can be formed in vitro from proteins not connected with these diseases, including the SH3 domain from bovine phosphatidyl-inositol-3′-kinase and the amino-terminal domain of the Escherichia coli HypF protein. Here we show that species formed early in the aggregation of these non-disease-associated proteins can be inherently highly cytotoxic. This finding provides added evidence that avoidance of protein aggregation is crucial for the preservation of biological function and suggests common features in the origins of this family of protein deposition diseases.

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Figure 1: PI3-SH3 aggregation and cytotoxicity.
Figure 2: HypF-N aggregation and cytotoxicity.
Figure 3: Percentage of cell deaths induced by 48-h-aged HypF-N aggregates at different protein concentrations.

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References

  1. Kelly, J. W. The alternative conformations of amyloidogenic proteins and their multi-step assembly pathways. Curr. Opin. Struct. Biol. 8, 101–106 (1998).

    Article  CAS  Google Scholar 

  2. Dobson, C. M. The structural basis of protein folding and its links with human disease. Phil. Trans. R. Soc. Lond. B 356, 133–145 (2001).

    Article  CAS  Google Scholar 

  3. Lambert, M. P. et al. Diffusible, nonfibrillar ligands derived from Aβ-42 are potent central nervous system neurotoxins. Proc. Natl Acad. Sci. USA 95, 6448–6453 (1998).

    Article  ADS  CAS  Google Scholar 

  4. Hartley, D. M. et al. Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J. Neurosci. 19, 8876–8884 (1999).

    Article  CAS  Google Scholar 

  5. Pillot, T. et al. The nonfibrillar amyloid β-peptide induces apoptotic neuronal cell death: involvement of its C-terminal fusogenic domain. J. Neurochem. 73, 1626–1634 (1999).

    Article  CAS  Google Scholar 

  6. Monji, A. et al. Inhibition of Aβ fibril formation and Aβ-induced cytotoxicity by senile plaque-associated proteins. Neurosci. Lett. 278, 81–84 (2000).

    Article  CAS  Google Scholar 

  7. Walsh, D. M. et al. Amyloid β-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J. Biol. Chem. 274, 25945–25952 (1999).

    Article  CAS  Google Scholar 

  8. Goldberg, M. S. & Lansbury, P. T. Jr Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson's disease? Nature Cell. Biol. 2, E115–E119 (2000).

    Article  CAS  Google Scholar 

  9. Conway, K. A. et al. Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc. Natl Acad. Sci. USA 97, 571—576 (2000).

    Article  Google Scholar 

  10. Zhu, Y. J., Lin, H. & Lal, R. Fresh and nonfibrillar amyloid beta protein(1–40) induces rapid cellular degeneration in aged human fibroblasts: evidence for A beta P-channel-mediated cellular toxicity. FASEB J. 14, 1244–1254 (2000).

    Article  CAS  Google Scholar 

  11. Pepys, M. B. in Oxford Textbook of Medicine (eds Weatherall, D. J., Ledingham, J. G. & Warrel, D. A.) 3rd edn, 1512–1524 (Oxford Univ. Press, Oxford, 1995).

    Google Scholar 

  12. Lorenzo, A. & Yankner, B. A. β-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc. Natl Acad. Sci. USA 91, 12243–12247 (1994).

    Article  ADS  CAS  Google Scholar 

  13. Thomas, T., Thomas, G., McLendon, C., Sutton, T. & Mullan, M. β-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380, 168–171 (1996).

    Article  ADS  CAS  Google Scholar 

  14. Clarke, G. et al. A one-hit model of cell death in inherited neuronal degenerations. Nature 406, 195–199 (2000).

    Article  ADS  CAS  Google Scholar 

  15. Perutz, M. F. & Windle, A. H. Cause of neuronal death in neurodegenerative disease attributable to expansion of glutamine repeats. Nature 412, 143–144 (2001).

    Article  ADS  CAS  Google Scholar 

  16. Glenner, G. G., Eanes, E. D., Bladen, H. A., Linke, R. P. & Termine, J. D. Beta-pleated sheet fibrils. A comparison of native amyloid with synthetic protein fibrils. J. Histochem. Cytochem. 22, 1141–1158 (1974).

    Article  CAS  Google Scholar 

  17. Guijarro, J. I., Sunde, M., Jones, J. A., Campbell, I. D. & Dobson, C. M. Amyloid fibril formation by an SH3 domain. Proc. Natl Acad. Sci. USA 95, 4224–4228 (1998).

    Article  ADS  CAS  Google Scholar 

  18. Chiti, F. et al. Designing conditions for in vitro formation of amyloid protofilaments and fibrils. Proc. Natl Acad. Sci. USA 96, 3590–3594 (1999).

    Article  ADS  CAS  Google Scholar 

  19. Fandrich, M., Fletcher, M. A. & Dobson, C. M. Amyloid fibrils from muscle myoglobin. Nature 410, 165–166 (2001).

    Article  ADS  CAS  Google Scholar 

  20. Chiti, F. et al. Solution conditions can promote formation of either amyloid protofilaments or mature fibrils from the HypF N-terminal domain. Protein Sci. 10, 2541–2547 (2001).

    Article  CAS  Google Scholar 

  21. Sunde, M. & Blake, C. F. The structure of amyloid fibrils by electron microscopy and X-ray diffraction. Adv. Protein Chem. 50, 123–159 (1997).

    Article  CAS  Google Scholar 

  22. Jimenez, J. L. et al. Cryo-electron microscopy structure of an SH3 amyloid fibril and model of the molecular packing. EMBO J. 18, 815–821 (1999).

    Article  CAS  Google Scholar 

  23. Liu, Y., Peterson, D. A., Kimura, H. & Schubert, D. Mechanism of cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. J. Neurochem. 69, 581–593 (1997).

    Article  CAS  Google Scholar 

  24. Abe, K. & Saito, H. Amyloid beta protein inhibits cellular MTT reduction not by suppression of mitochondrial succinate dehydrogenase but by acceleration of MTT formazan exocytosis in cultured rat cortical astrocytes. Neurosci. Res. 31, 295–305 (1998).

    Article  CAS  Google Scholar 

  25. Harper, J. D., Lieber, C. M. & Lansbury, P. T. Jr Atomic force microscopy imaging of seeded fibril formation and fibril branching by Alzheimer's disease amyloid-β protein. Chem. Biol. 4, 951–959 (1997).

    Article  CAS  Google Scholar 

  26. Mendes Sousa, M., Cardoso, I., Fernandes, R., Guimaraes, A. & Saraiva, M. J. Deposition of transthyretin in early stages of familial amylodotic polyneuropathy. Evidence for toxicity of nonfibrillar aggregates. Am. J. Pathol. 159, 1993–2000 (2001).

    Article  Google Scholar 

  27. Fezoui, Y. et al. A de novo designed helix-turn-helix peptide forms non-toxic amyloid fibrils. Nature Struct. Biol. 7, 1095–1099 (2000).

    Article  CAS  Google Scholar 

  28. Hsia, A. Y. et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc. Natl Acad. Sci. USA 96, 3228–3233 (1999).

    Article  ADS  CAS  Google Scholar 

  29. Zurdo, J., Guijarro, J. I. & Dobson, C. M. Preparation and characterisation of purified amyloid fibrils. J. Am. Chem. Soc. 123, 8141–8142 (2001).

    Article  CAS  Google Scholar 

  30. Leroux, M. R. & Hartl, F. U. in Mechanisms of Protein Folding (ed. Pain, R. H.) 2nd edn, 364–405 (Oxford Univ. Press, Oxford, 1999).

    Google Scholar 

  31. Sherman, M. Y. & Goldberg, A. L. Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 29, 15–32 (2001).

    Article  CAS  Google Scholar 

  32. Li, L. R. & Lindquist, S. Creating a protein-based element of inheritance. Science 287, 661–664 (2000).

    Article  ADS  CAS  Google Scholar 

  33. Booker, J. W. et al. Solution structure and ligand-binding site of the SH3 domain of the P85 alpha-subunit of phosphatidylinositil-3-kinase. Cell 73, 813–822 (1993).

    Article  CAS  Google Scholar 

  34. Butterfield, D. A., Yatin, S. M., Varadarajan, S. & Koppal, T. Amyloid β-peptide-associated free radical oxidative stress, neurotoxicity and Alzheimer's disease. Methods Enzymol. 309, 746–768 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work was supported by grants from the Italian MIUR (PRIN “Folding e Misfolding di Proteine) and the Italian Telethon Foundation. The research of C.M.D. is supported in part by a Programme Grant from the Wellcome Trust. F.C. is supported by a fellowship from the Italian Telethon Foundation.

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Author notes

  1. Monica Bucciantini, Elisa Giannoni, Fabrizio Chiti, Jesús Zurdo and Christopher M. Dobson: These authors contributed equally to this work

Authors and Affiliations

  1. Dipartimento di Scienze Biochimiche, Universitá degli Studi di Firenze, Viale Morgagni 50, Firenze, 50134, Italy

    Monica Bucciantini, Elisa Giannoni, Fabrizio Chiti, Fabiana Baroni, Niccolò Taddei, Giampietro Ramponi & Massimo Stefani

  2. Dipartimento di Anatomia, Istologia e Medicina legale, Universitá degli Studi di Firenze, Viale Morgagni 85, Firenze, 50134, Italy

    Lucia Formigli

  3. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK

    Fabrizio Chiti, Jesús Zurdo & Christopher M. Dobson

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  1. Monica Bucciantini
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Correspondence to Christopher M. Dobson or Massimo Stefani.

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Bucciantini, M., Giannoni, E., Chiti, F. et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416, 507–511 (2002). https://doi.org/10.1038/416507a

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