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Inhibition of α‐synuclein aggregation by small heat shock proteins
Author(s) -
Bruinsma Ilona B.,
Bruggink Kim A.,
Kinast Karsten,
Versleijen Alexandra A. M.,
SegersNolten Ine M. J.,
Subramaniam Vinod,
Bea Kuiperij H.,
Boelens Wilbert,
de Waal Robert M. W.,
Verbeek Marcel M.
Publication year - 2011
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.23152
Subject(s) - synucleinopathies , fibril , protein aggregation , mutant , biophysics , protein folding , heat shock protein , chemistry , pathogenesis , microbiology and biotechnology , hsp27 , thioflavin , chaperone (clinical) , alpha synuclein , biochemistry , biology , hsp70 , parkinson's disease , disease , medicine , gene , alzheimer's disease , immunology , pathology
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.