Inhibition of alpha-synuclein aggregation by small heat shock proteins

Ilona B. Bruinsma, Kim A. Bruggink, Karsten Kinast, Alexandra A.M. Versleijen, Gezina M.J. Segers-Nolten, Vinod Subramaniam, H. Bea Kuiperij, Wilbert Boelens, Robert M.W. de Waal, Marcel M. Verbeek

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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
Original languageUndefined
Pages (from-to)2956-2967
Number of pages12
Issue number10
Publication statusPublished - 2011


  • IR-96431
  • METIS-279005

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