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dc.contributor.authorFarzadfard, Azad
dc.contributor.authorPedersen, Jannik Nedergaard
dc.contributor.authorMeisl, Georg
dc.contributor.authorSomavarapu, Arun Kumar
dc.contributor.authorAlam, Parvez
dc.contributor.authorGoksøyr, Louise
dc.contributor.authorNielsen, Morten Agertoug
dc.contributor.authorSander, Adam Frederik
dc.contributor.authorKnowles, Tuomas
dc.contributor.authorPedersen, Jan Skov
dc.contributor.authorOtzen, Daniel Erik
dc.date.accessioned2022-02-10T16:20:29Z
dc.date.available2022-02-10T16:20:29Z
dc.date.issued2022-02-10
dc.date.submitted2021-06-15
dc.identifier.issn2399-3642
dc.identifier.others42003-022-03059-8
dc.identifier.other3059
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/333848
dc.description.abstractAggregation of the 140-residue protein α-synuclein (αSN) is a key factor in the etiology of Parkinson's disease. Although the intensely anionic C-terminal domain (CTD) of αSN does not form part of the amyloid core region or affect membrane binding ability, truncation or reduction of charges in the CTD promotes fibrillation through as yet unknown mechanisms. Here, we study stepwise truncated CTDs and identify a threshold region around residue 121; constructs shorter than this dramatically increase their fibrillation tendency. Remarkably, these effects persist even when as little as 10% of the truncated variant is mixed with the full-length protein. Increased fibrillation can be explained by a substantial increase in self-replication, most likely via fragmentation. Paradoxically, truncation also suppresses toxic oligomer formation, and oligomers that can be formed by chemical modification show reduced membrane affinity and cytotoxicity. These remarkable changes correlate to the loss of negative electrostatic potential in the CTD and highlight a double-edged electrostatic safety guard.
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectArticle
dc.subject/631/57
dc.subject/631/337
dc.subject/82/16
dc.subject/82/29
dc.subject/82/80
dc.subject/82/83
dc.subject/101/28
dc.subjectarticle
dc.titleThe C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization.
dc.typeArticle
dc.date.updated2022-02-10T16:20:29Z
prism.issueIdentifier1
prism.publicationNameCommun Biol
prism.volume5
dc.identifier.doi10.17863/CAM.81264
dcterms.dateAccepted2022-01-18
rioxxterms.versionofrecord10.1038/s42003-022-03059-8
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidMeisl, Georg [0000-0002-6562-7715]
dc.contributor.orcidGoksøyr, Louise [0000-0003-4508-9857]
dc.contributor.orcidNielsen, Morten Agertoug [0000-0003-2668-4992]
dc.contributor.orcidSander, Adam Frederik [0000-0002-8782-7830]
dc.contributor.orcidKnowles, Tuomas [0000-0002-7879-0140]
dc.contributor.orcidPedersen, Jan Skov [0000-0002-7768-0206]
dc.contributor.orcidOtzen, Daniel Erik [0000-0002-2918-8989]
dc.identifier.eissn2399-3642
cam.issuedOnline2022-02-10


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