Show simple item record

dc.contributor.authorPorcari, Ren
dc.contributor.authorProukakis, Cen
dc.contributor.authorWaudby, CAen
dc.contributor.authorBolognesi, Ben
dc.contributor.authorMangione, PPen
dc.contributor.authorPaton, JFSen
dc.contributor.authorMullin, Sen
dc.contributor.authorCabrita, LDen
dc.contributor.authorPenco, Aen
dc.contributor.authorRelini, Aen
dc.contributor.authorVerona, Gen
dc.contributor.authorVendruscolo, Men
dc.contributor.authorStoppini, Men
dc.contributor.authorTartaglia, GGen
dc.contributor.authorCamilloni, Cen
dc.contributor.authorChristodoulou, Jen
dc.contributor.authorSchapira, AHVen
dc.contributor.authorBellotti, Ven
dc.date.accessioned2021-01-12T15:23:32Z
dc.date.available2021-01-12T15:23:32Z
dc.date.issued2015-01-23en
dc.identifier.urihttp://hdl.handle.net/10026.1/16798
dc.description.abstract

The conversion of α-synuclein from its intrinsically disordered monomeric state into the fibrillar cross-β aggregates characteristically present in Lewy bodies is largely unknown. The investigation of α-synuclein variants causative of familial forms of Parkinson disease can provide unique insights into the conditions that promote or inhibit aggregate formation. It has been shown recently that a newly identified pathogenic mutation of α-synuclein, H50Q, aggregates faster than the wild-type. We investigate here its aggregation propensity by using a sequence-based prediction algorithm, NMR chemical shift analysis of secondary structure populations in the monomeric state, and determination of thermodynamic stability of the fibrils. Our data show that the H50Q mutation induces only a small increment in polyproline II structure around the site of the mutation and a slight increase in the overall aggregation propensity. We also find, however, that the H50Q mutation strongly stabilizes α-synuclein fibrils by 5.0 ± 1.0 kJ mol(-1), thus increasing the supersaturation of monomeric α-synuclein within the cell, and strongly favors its aggregation process. We further show that wild-type α-synuclein can decelerate the aggregation kinetics of the H50Q variant in a dose-dependent manner when coaggregating with it. These last findings suggest that the precise balance of α-synuclein synthesized from the wild-type and mutant alleles may influence the natural history and heterogeneous clinical phenotype of Parkinson disease.

en
dc.format.extent2395 - 2404en
dc.languageengen
dc.language.isoengen
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.subjectAggregation Propensityen
dc.subjectAmyloiden
dc.subjectFibrilen
dc.subjectFibrils Thermodynamic Stabilityen
dc.subjectParkinson Diseaseen
dc.subjectPolyproline II Structureen
dc.subjectProtein Aggregationen
dc.subjectalpha-Synuclein (a-synuclein)en
dc.subjectAmyloiden
dc.subjectBinding Sitesen
dc.subjectHumansen
dc.subjectLewy Bodiesen
dc.subjectMagnetic Resonance Spectroscopyen
dc.subjectMicroscopy, Atomic Forceen
dc.subjectMutationen
dc.subjectParkinson Diseaseen
dc.subjectPeptidesen
dc.subjectPhenotypeen
dc.subjectProtein Bindingen
dc.subjectProtein Isoformsen
dc.subjectProtein Structure, Secondaryen
dc.subjectRecombinant Proteinsen
dc.subjectSolubilityen
dc.subjectThermodynamicsen
dc.subjectalpha-Synucleinen
dc.titleThe H50Q mutation induces a 10-fold decrease in the solubility of α-synuclein.en
dc.typeJournal Article
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/25505181en
plymouth.issue4en
plymouth.volume290en
plymouth.publication-statusPublisheden
plymouth.journalJ Biol Chemen
dc.identifier.doi10.1074/jbc.M114.610527en
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
dc.publisher.placeUnited Statesen
dc.identifier.eissn1083-351Xen
dc.rights.embargoperiodNot knownen
rioxxterms.versionofrecord10.1074/jbc.M114.610527en
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by-nc/4.0/en
rioxxterms.typeJournal Article/Reviewen


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record

Attribution-NonCommercial 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial 4.0 International

All items in PEARL are protected by copyright law.
Author manuscripts deposited to comply with open access mandates are made available in accordance with publisher policies. Please cite only the published version using the details provided on the item record or document. In the absence of an open licence (e.g. Creative Commons), permissions for further reuse of content should be sought from the publisher or author.
Theme by 
@mire NV