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

Nature. 2002 Apr 4;416(6880):507-11. doi: 10.1038/416507a.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Alzheimer Disease / etiology
  • Alzheimer Disease / pathology
  • Animals
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / toxicity
  • Bacterial Proteins / ultrastructure
  • Biological Evolution
  • Cytotoxins
  • Humans
  • Mice
  • Neurodegenerative Diseases / etiology*
  • Neurodegenerative Diseases / metabolism
  • PC12 Cells
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / ultrastructure
  • Plaque, Amyloid / chemistry*
  • Plaque, Amyloid / metabolism
  • Protein Folding*
  • Rats
  • Recombinant Proteins / chemistry
  • src Homology Domains


  • Bacterial Proteins
  • Cytotoxins
  • HypF protein, Bacteria
  • Recombinant Proteins
  • Phosphatidylinositol 3-Kinases