What the use of disease-unrelated model proteins can tell us about the molecular basis of amyloid aggregation and toxicity.

Recent advances in the studies on protein aggregation have led to a reappraisal of the concepts underlying this process. The data reported in the last few years showing that protein aggregation into assemblies of amyloid type can be considered a generic property of the polypeptide chains suggest that protein aggregation in cells can be a more common phenomenon than previously believed. Furthermore, the findings that aggregates of disease-unrelated proteins display the same cytotoxicity as those formed by proteins and peptides associated with disease suggest that toxicity is a consequence of the common structure of aggregates and that, at least in most cases, it proceeds by impairing common cellular parameters such as free Ca2+ and ROS levels. The new view that aggregation of polypeptide chains and aggregate toxicity are not linked to specific amino acid sequences rises dramatically the number of sequences one can investigate to assess the molecular features underlying protein aggregation and the molecular basis of aggregate toxicity. In addition, it rises intriguing considerations on protein and cell evolution as well as on amyloid disease pathogenesis.