Inhibition of α-synuclein aggregation by small heat shock proteins

Proteins. 2011 Oct;79(10):2956-67. doi: 10.1002/prot.23152. Epub 2011 Aug 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HSP27 Heat-Shock Proteins / metabolism
  • Heat-Shock Proteins / metabolism
  • Heat-Shock Proteins, Small / metabolism*
  • Humans
  • Microscopy, Atomic Force
  • Molecular Chaperones
  • Mutation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • Surface Plasmon Resonance
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*


  • HSP27 Heat-Shock Proteins
  • HSPB2 protein, human
  • HSPB3 protein, human
  • HSPB8 protein, human
  • Heat-Shock Proteins
  • Heat-Shock Proteins, Small
  • Molecular Chaperones
  • alpha-Synuclein
  • Protein-Serine-Threonine Kinases