Abstract
The fibrillization of α‐synuclein (α‐syn) is a key event in the pathogenesis of α‐synucleinopathies. Mutant α‐syn (A53T, A30P, or E46K), each linked to familial Parkinson's disease, has altered aggregation properties, fibril morphologies, and fibrillization kinetics. Besides α‐syn, Lewy bodies also contain several associated proteins including small heat shock proteins (sHsps). Since α‐syn accumulates intracellularly, molecular chaperones like sHsps may regulate α‐syn folding and aggregation. Therefore, we investigated if the sHsps αB‐crystallin, Hsp27, Hsp20, HspB8, and HspB2B3 bind to α‐syn and affect α‐syn aggregation. We demonstrate that all sHsps bind to the various α‐syns, although the binding kinetics suggests a weak and transient interaction only. Despite this transient interaction, the various sHsps inhibited mature α‐syn fibril formation as shown by a Thioflavin T assay and atomic force microscopy. Interestingly, HspB8 was the most potent sHsp in inhibiting mature fibril formation of both wild‐type and mutant α‐syn. In conclusion, sHsps may regulate α‐syn aggregation and, therefore, optimization of the interaction between sHsps and α‐syn may be an interesting target for therapeutic intervention in the pathogenesis of α‐synucleinopathies. Proteins 2011; © 2011 Wiley‐Liss, Inc.