Skip to main content

Thank you for visiting 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.

Folding proteins in fatal ways

An Erratum to this article was published on 25 March 2004


Human diseases characterized by insoluble extracellular deposits of proteins have been recognized for almost two centuries. Such amyloidoses were once thought to represent arcane secondary phenomena of questionable pathogenic significance. But it is has now become clear that many different proteins can misfold and form extracellular or intracellular aggregates that initiate profound cellular dysfunction. Particularly challenging examples of such disorders occur in the post-mitotic environment of the neuron and include Alzheimer's and Parkinson's diseases. Understanding some of the principles of protein folding has helped to explain how such diseases arise, with attendant therapeutic insights.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Proposed mechanism for lysozyme amyloid fibril formation.


  1. Glenner, G. G. Amyloid deposits and amyloidosis: the β-fibrilloses (first of two parts). N. Engl. J. Med. 302, 1283–1292 (1980).

    Article  CAS  Google Scholar 

  2. Glenner, G. G. Amyloid deposits and amyloidosis: the β-fibrilloses (second of two parts). N. Engl. J. Med. 302, 1333–1343 (1980).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. Bucciantini, M. et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416, 507–511 (2002).

    Article  ADS  CAS  Google Scholar 

  5. 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 

  6. Jarrett, J. T. & Lansbury, P. T. Seeding 'one-dimensional crystallization' of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73, 1055–1058 (1993).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  8. Zoghbi, H. Y. & Orr, H. T. Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23, 217–247 (2000).

    Article  CAS  Google Scholar 

  9. Selkoe, D. J. & Podlisny, M. B. Deciphering the genetic basis of Alzheimer's disease. Annu. Rev. Genomics Hum. Genet. 3, 67–99 (2002).

    Article  CAS  Google Scholar 

  10. Hutton, M. Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neurology 56, S21–S25 (2001).

    Article  CAS  Google Scholar 

  11. Prusiner, S. B. Neurodegenerative diseases and prions. N. Engl. J. Med. 344, 1516–1526 (2001).

    Article  CAS  Google Scholar 

  12. Booth, D. R. et al. Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 385, 787–793 (1997).

    Article  ADS  CAS  Google Scholar 

  13. Haezebrouck, P. et al. An equilibrium partially folded state of human lysozyme at low pH. J. Mol. Biol. 246, 382–387 (1995).

    Article  CAS  Google Scholar 

  14. Radford, S. E. & Dobson, C. M. Insights into protein folding using physical techniques: studies of lysozyme and α-lactalbumin. Phil. Trans. R. Soc. Lond. B 348, 17–25 (1995).

    Article  ADS  CAS  Google Scholar 

  15. Riek, R. et al. NMR structure of the mouse prion protein domain PrP(121–231). Nature 382, 180–182 (1996).

    Article  ADS  CAS  Google Scholar 

  16. 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 

  17. Mucke, L. et al. High-level neuronal expression of Aβ 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058 (2000).

    Article  CAS  Google Scholar 

  18. Naslund, J. et al. Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline. J. Am. Med. Assoc. 283, 1571–1577 (2000).

    Article  CAS  Google Scholar 

  19. Kuo, Y.-M. et al. Water-soluble Aβ (N-40, N-42) oligomers in normal and Alzheimer disease brains. J. Biol. Chem. 271, 4077–4081 (1996).

    Article  CAS  Google Scholar 

  20. Lue, L. F. et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am. J. Pathol. 155, 853–862 (1999).

    Article  ADS  CAS  Google Scholar 

  21. Selkoe, D. J. Alzheimer's disease is a synaptic failure. Science 298, 789–791 (2002).

    Article  ADS  CAS  Google Scholar 

  22. Walsh, D. et al. Naturally secreted oligomers of the Alzheimer amyloid β-protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).

    Article  ADS  CAS  Google Scholar 

  23. Watase, K. et al. A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 34, 905–919 (2002).

    Article  CAS  Google Scholar 

  24. Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., Lee, V. M. & Bonini, N. M. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295, 865–868 (2002).

    Article  ADS  CAS  Google Scholar 

  25. Warrick, J. M. et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nature Genet. 23, 425–428 (1999).

    Article  CAS  Google Scholar 

  26. Opal, P. & Zoghbi, H. Y. The role of chaperones in polyglutamine disease. Trends Mol. Med. 8, 232–236 (2002).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

Reprints and Permissions

About this article

Cite this article

Selkoe, D. Folding proteins in fatal ways. Nature 426, 900–904 (2003).

Download citation

  • Issue Date:

  • DOI:

This article is cited by


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.


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