Inhibition of α-synuclein aggregation by small heat shock proteins

The fibrillization of alpha-synuclein (alpha-syn) is a key event in the pathogenesis of alpha-synucleinopathies. Mutant alpha-syn (A53T, A30P, or E46K), each linked to familial Parkinson's disease, has altered aggregation properties, fibril morphologies, and fibrillization kinetics. Besides alpha-syn, Lewy bodies also contain several associated proteins including small heat shock proteins (sHsps). Since alpha-syn accumulates intracellularly, molecular chaperones like sHsps may regulate alpha-syn folding and aggregation. Therefore, we investigated if the sHsps alpha B-crystallin, Hsp27, Hsp20, HspB8, and HspB2B3 bind to alpha-syn and affect alpha-syn aggregation. We demonstrate that all sHsps bind to the various alpha-syns, although the binding kinetics suggests a weak and transient interaction only. Despite this transient interaction, the various sHsps inhibited mature alpha-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 alpha-syn. In conclusion, sHsps may regulate alpha(-)syn aggregation and, therefore, optimization of the interaction between sHsps and alpha-syn may be an interesting target for therapeutic intervention in the pathogenesis of alpha-synucleinopathies.