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dc.contributor.authorIljina, Marija
dc.contributor.authorDear, Alexander J
dc.contributor.authorGarcia, Gonzalo A
dc.contributor.authorDe, Suman
dc.contributor.authorTosatto, Laura
dc.contributor.authorFlagmeier, Patrick
dc.contributor.authorWhiten, Daniel R
dc.contributor.authorMichaels, Thomas
dc.contributor.authorFrenkel, Daan
dc.contributor.authorDobson, Christopher
dc.contributor.authorKnowles, Tuomas
dc.contributor.authorKlenerman, David
dc.date.accessioned2018-12-08T00:30:54Z
dc.date.available2018-12-08T00:30:54Z
dc.date.issued2018-11-27
dc.identifier.issn1936-0851
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286525
dc.description.abstractSmall oligomers of the protein α-synuclein (αS) are highly cytotoxic species associated with Parkinson's disease (PD). In addition, αS can form co-aggregates with its mutational variants and with other proteins such as amyloid-β (Aβ) and tau, which are implicated in Alzheimer's disease. The processes of self-oligomerization and co-oligomerization of αS are, however, challenging to study quantitatively. Here, we have utilized single-molecule techniques to measure the equilibrium populations of oligomers formed in vitro by mixtures of wild-type αS with its mutational variants and with Aβ40, Aβ42, and a fragment of tau. Using a statistical mechanical model, we find that co-oligomer formation is generally more favorable than self-oligomer formation at equilibrium. Furthermore, self-oligomers more potently disrupt lipid membranes than do co-oligomers. However, this difference is sometimes outweighed by the greater formation propensity of co-oligomers when multiple proteins coexist. Our results suggest that co-oligomer formation may be important in PD and related neurodegenerative diseases.
dc.description.sponsorshipThe authors are grateful for financial support provided by Dr Tayyeb Hussain Scholarship and the ERC (669237) (M. Iljina), the Schiff Foundation (A. Dear), Alzheimer’s Research UK and Marie-Curie Individual Fellowship (S. De), a fellowship from Fondazione Caritro, Trento (BANDO 2017 PER PROGETTI DI RICERCA SVOLTI DA GIOVANI RICERCATORI POST-DOC) (L. Tosatto), the Boehringer Ingelheim Fonds and the Studienstiftung des deutschen Volkes (P. Flagmeier), the Centre for Misfolding Diseases (A. Dear, P. Flagmeier, C. Dobson, T. Knowles), the ERC (669237) and the Royal Society (D. Klenerman). We are grateful to S. Preet for the expression and purification of A90C ɑS. We thank Y. Ye for providing tau k18.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherAmerican Chemical Society (ACS)
dc.subjectHumans
dc.subjecttau Proteins
dc.subjectThermodynamics
dc.subjectModels, Molecular
dc.subjectalpha-Synuclein
dc.subjectAmyloid beta-Peptides
dc.titleQuantifying Co-Oligomer Formation by α-Synuclein.
dc.typeArticle
prism.endingPage10866
prism.issueIdentifier11
prism.publicationDate2018
prism.publicationNameACS Nano
prism.startingPage10855
prism.volume12
dc.identifier.doi10.17863/CAM.33835
dcterms.dateAccepted2018-10-24
rioxxterms.versionofrecord10.1021/acsnano.8b03575
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-11
dc.contributor.orcidIljina, Marija [0000-0002-0824-3707]
dc.contributor.orcidDe, Suman [0000-0003-1675-0773]
dc.contributor.orcidFlagmeier, Patrick [0000-0002-1204-5340]
dc.contributor.orcidMichaels, Thomas [0000-0001-6931-5041]
dc.contributor.orcidFrenkel, Daan [0000-0002-6362-2021]
dc.contributor.orcidKnowles, Tuomas [0000-0002-7879-0140]
dc.contributor.orcidKlenerman, David [0000-0001-7116-6954]
dc.identifier.eissn1936-086X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idEuropean Research Council (669237)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (701013)
cam.issuedOnline2018-10-29
cam.orpheus.successThu Jan 30 10:53:42 GMT 2020 - The item has an open VoR version.
rioxxterms.freetoread.startdate2100-01-01


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