Inhibition of α-synuclein aggregation by small heat shock proteins

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

    Research output: Contribution to JournalArticleAcademicpeer-review


    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 languageEnglish
    Pages (from-to)2956-67
    Number of pages12
    Issue number10
    Publication statusPublished - Oct 2011


    • HSP27 Heat-Shock Proteins
    • Heat-Shock Proteins
    • Heat-Shock Proteins, Small
    • Humans
    • Microscopy, Atomic Force
    • Mutation
    • Protein Binding
    • Protein-Serine-Threonine Kinases
    • Surface Plasmon Resonance
    • alpha-Synuclein
    • Journal Article
    • Research Support, Non-U.S. Gov't


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