Protein aggregation can proceed via disordered or ordered mechanisms, with the latter being associated with
amyloid fibril formation, which has been linked to a number of debilitating conditions including Alzheimer's, Parkinson's and Creutzfeldt-Jakob diseases.
Small heat-shock proteins (sHsps), such as alphaB-
crystallin, act as chaperones to prevent
protein aggregation and are thought to play a key role in the prevention of
protein-misfolding diseases. In this study, we have explored the potential for small molecules such as
arginine and
guanidine to affect the chaperone activity of alphaB-
crystallin against disordered (amorphous) and ordered (
amyloid fibril) forms of
protein aggregation. The effect of these additives is highly dependent upon the target
protein undergoing aggregation. Importantly, our results show that the chaperone action of alphaB-
crystallin against aggregation of the disease-related
amyloid fibril forming
protein alpha-synucleinA53T is enhanced in the presence of
arginine and similar positively charged compounds (such as
lysine and
guanidine). Thus, our results suggest that target
protein identity plays a critical role in governing the effect of small molecules on the chaperone action of sHsps. Significantly, small molecules that regulate the activity of sHsps may provide a mechanism to protect cells from the toxic
protein aggregation that is associated with some
protein-misfolding diseases.