title: Small Heat-shock Proteins Prevent α-Synuclein Aggregation via Transient Interactions and Their Efficacy Is Affected by the Rate of Aggregation.
abstract: The aggregation of α-synuclein (α-syn) into amyloid fibrils is associated with neurodegenerative diseases, collectively referred to as the α-synucleinopathies. In vivo, molecular chaperones, such as the small heat-shock proteins (sHsps), normally act to prevent protein aggregation; however, it remains to be determined how aggregation-prone α-syn evades sHsp chaperone action leading to its disease-associated deposition. This work examines the molecular mechanism by which two canonical sHsps, αB-crystallin (αB-c) and Hsp27, interact with aggregation-prone α-syn to prevent its aggregation in vitro Both sHsps are very effective inhibitors of α-syn aggregation, but no stable complex between the sHsps and α-syn was detected, indicating that the sHsps inhibit α-syn aggregation via transient interactions. Moreover, the ability of these sHsps to prevent α-syn aggregation was dependent on the kinetics of aggregation; the faster the rate of aggregation (shorter the lag phase), the less effective the sHsps were at inhibiting fibril formation of α-syn. Thus, these findings indicate that the rate at which α-syn aggregates in cells may be a significant factor in how it evades sHsp chaperone action in the α-synucleinopathies.
authors: From the Illawarra Health and Medical Research Institute and.|School of Biological Sciences, University of Wollongong, Wollongong, New South Wales 2522.
authors: Dezerae
authors: D
authors: Cox
authors: the Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, and.
authors: Emily
authors: E
authors: Selig
authors: the Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, and.
authors: Michael D W
authors: MD
authors: Griffin
authors: the Research School of Chemistry, The Australian National University, Acton, Australian Capital Territory 2601, Australia.
authors: John A
authors: JA
authors: Carver
authors: From the Illawarra Health and Medical Research Institute and heathe@uow.edu.au.|School of Biological Sciences, University of Wollongong, Wollongong, New South Wales 2522.
authors: Heath
authors: H
authors: Ecroyd
mesh_terms: D055551:HSP27 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D018832:Molecular Chaperones; D066329:Protein Aggregates; D038203:alpha-Crystallin B Chain / Q000737:chemistry* / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D066329:Protein Aggregates; C497604:SNCA protein, human; D038203:alpha-Crystallin B Chain; D051844:alpha-Synuclein
keywords: Parkinson disease; amyloid; analytical ultracentrifugation; fibril; molecular chaperone; protein aggregation; small heat shock protein (sHsp); synuclein; α-synuclein (a-synuclein)