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.
Scientists have shown 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.
Findings, that early aggregates formed by a wider range of proteins than those known to be associated with neurological diseases can be cytotoxic, provide new opportunities to define the nature of amyloid diseases and the mechanism of amyloid toxicity at the molecular level.
They also raise the possibility that trace amounts of aggregates of a variety of proteins might occur spontaneously, particularly during ageing, and that such aggregates could account for subtle impairments of cellular function in the absence of an evident amyloid phenotype.
It would thus be interesting to search for early protein aggregates in systemic and neurological disorders not presently associated with amyloid formation.
More generally, knowledge of the origin and nature of aggregate pathogenicity is of crucial importance in efforts to identify the correct targets for drug design in the search for effective therapeutic protocols.
The inherent toxicity in protein aggregates could also help us to understand fundamental aspects of cell biology.
It suggests, for example, that avoidance of aggregation could be more important for the proper functioning of biological organisms than was previously suspected if aggregates of proteins are often toxic rather than simply non-functional.
In this case, in addition to increasing the efficiency of folding and rescuing misfolded proteins after biosynthesis, evolutionary developments to prevent aggregate formation, notably molecular chaperones, ubiquitination enzymes and proteasomes, are needed for the preservation of the long-term viability of living organisms.
This latter idea is reinforced by recent findings concerning the relationships between neurodegenerative diseases and failure of cellular defense mechanisms targeted towards misfolded proteins and the existence, in both prokaryotic and eukaryotic cells, of a complex regulatory system of intracellular protein degradation.
Such results, together with findings that aggregate formation is linked to the inheritance of specific traits in organisms such as yeasts, provides increasing evidence that the control of protein misfolding and aggregation in addition to being of fundamental importance for cell viability, has been a major driving force in biological evolution.