Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution

Abstract

The deposition of proteins in the form of amyloid fibrils and plaques is the characteristic feature of more than 20 degenerative conditions affecting either the central nervous system or a variety of peripheral tissues. As these conditions include Alzheimer's, Parkinson's and the prion diseases, several forms of fatal systemic amyloidosis, and at least one condition associated with medical intervention (haemodialysis), they are of enormous importance in the context of present-day human health and welfare. Much remains to be learned about the mechanism by which the proteins associated with these diseases aggregate and form amyloid structures, and how the latter affect the functions of the organs with which they are associated. A great deal of information concerning these diseases has emerged, however, during the past 5 years, much of it causing a number of fundamental assumptions about the amyloid diseases to be re-examined. For example, it is now apparent that the ability to form amyloid structures is not an unusual feature of the small number of proteins associated with these diseases but is instead a general property of polypeptide chains. It has also been found recently that aggregates of proteins not associated with amyloid diseases can impair the ability of cells to function to a similar extent as aggregates of proteins linked with specific neurodegenerative conditions. Moreover, the mature amyloid fibrils or plaques appear to be substantially less toxic than the pre-fibrillar aggregates that are their precursors. The toxicity of these early aggregates appears to result from an intrinsic ability to impair fundamental cellular processes by interacting with cellular membranes, causing oxidative stress and increases in free Ca2+ that eventually lead to apoptotic or necrotic cell death. The 'new view' of these diseases also suggests that other degenerative conditions could have similar underlying origins to those of the amyloidoses. In addition, cellular protection mechanisms, such as molecular chaperones and the protein degradation machinery, appear to be crucial in the prevention of disease in normally functioning living organisms. It also suggests some intriguing new factors that could be of great significance in the evolution of biological molecules and the mechanisms that regulate their behaviour.

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

“…Approximately 24 human proteins form amyloid fibrils in vivo (Stefani & Dobson, 2003). These proteins are unrelated at the level of primary structure, consistent with the finding that many proteins with no connection to disease can form amyloid fibrils with a common core structure in vitro, suggesting that the amyloid fibril is an intrinsically stable structure (Dobson, 2001).…”

The effects of shear flow on protein structure and function

“…The energy threshold between the native and denatured state of a protein is low, thus the physicochemical environment is a critical determinant of protein structure and function. 1 Perturbation of the native protein conformation results in loss of catalytic activity or biological function, 2,3 and in many cases aggregation and amyloid fibril formation. [4][5][6] Structural perturbation of protein molecules occurs as a result of conditions of temperature, pH, and ionic strength as well as through the presence of denaturants (e.g., urea, guanidine), organic solvents, and surfactants.…”

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

“…Misfolding of amyloidogenic proteins gives rise to self-assembled aggregates [1]. Whereas monomeric forms are not toxic, these aggregates have been identified as toxic species responsible for the disease.…”