title: Inhibition of α-synuclein aggregation by small heat shock proteins.
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.
authors: Department of Neurology and Alzheimer Centre, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. i.bruinsma@neuro.umcn.nl
authors: Ilona B
authors: IB
authors: Bruinsma
authors: Kim A
authors: KA
authors: Bruggink
authors: Karsten
authors: K
authors: Kinast
authors: Alexandra A M
authors: AA
authors: Versleijen
authors: Ine M J
authors: IM
authors: Segers-Nolten
authors: Vinod
authors: V
authors: Subramaniam
authors: H Bea
authors: HB
authors: Kuiperij
authors: Wilbert
authors: W
authors: Boelens
authors: Robert M W
authors: RM
authors: de Waal
authors: Marcel M
authors: MM
authors: Verbeek
mesh_terms: D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D050888:Heat-Shock Proteins, Small / Q000378:metabolism*; D006801:Humans; D018625:Microscopy, Atomic Force; D018832:Molecular Chaperones; D009154:Mutation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020349:Surface Plasmon Resonance; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D055551:HSP27 Heat-Shock Proteins; C442250:HSPB2 protein, human; C116424:HSPB3 protein, human; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D050888:Heat-Shock Proteins, Small; D018832:Molecular Chaperones; D051844:alpha-Synuclein; D017346:Protein Serine-Threonine Kinases