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Small Heat-shock Proteins Prevent -Synuclein Aggregation via Transient Interactions and Their Efficacy Is Affected by the Rate of Aggregation

Cox, Dezerae; Selig, Emily; Griffin, Michael D.W.; Carver, John; Ecroyd, Heath

Description

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,...[Show more]

dc.contributor.authorCox, Dezerae
dc.contributor.authorSelig, Emily
dc.contributor.authorGriffin, Michael D.W.
dc.contributor.authorCarver, John
dc.contributor.authorEcroyd, Heath
dc.date.accessioned2018-11-29T22:54:40Z
dc.date.available2018-11-29T22:54:40Z
dc.identifier.issn1083-351X
dc.identifier.urihttp://hdl.handle.net/1885/152872
dc.description.abstractThe 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.
dc.format.mimetypeapplication/pdf
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc
dc.sourceJournal of Biological Chemistry
dc.titleSmall Heat-shock Proteins Prevent -Synuclein Aggregation via Transient Interactions and Their Efficacy Is Affected by the Rate of Aggregation
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume291
dc.date.issued2016
local.identifier.absfor030406 - Proteins and Peptides
local.identifier.ariespublicationu8801298xPUB231
local.type.statusPublished Version
local.contributor.affiliationCox, Dezerae, University of Wollongong
local.contributor.affiliationSelig, Emily, The University of Melbourne
local.contributor.affiliationGriffin, Michael D.W., University of Melbourne
local.contributor.affiliationCarver, John, College of Science, ANU
local.contributor.affiliationEcroyd, Heath, University of Wollongong
local.bibliographicCitation.issue43
local.bibliographicCitation.startpage22618
local.bibliographicCitation.lastpage22629
local.identifier.doi10.1074/jbc.M116.739250
local.identifier.absseo970103 - Expanding Knowledge in the Chemical Sciences
dc.date.updated2018-11-29T08:01:30Z
local.identifier.scopusID2-s2.0-84992316267
local.identifier.thomsonID000386760600022
dcterms.accessRightsOpen Access
CollectionsANU Research Publications

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