Show simple item record

dc.contributor.authorLudtmann, Marthe HR
dc.contributor.authorAngelova, Plamena R
dc.contributor.authorHorrocks, Mathew
dc.contributor.authorChoi, Minee L
dc.contributor.authorRodrigues, Margarida
dc.contributor.authorBaev, Artyom Y
dc.contributor.authorBerezhnov, Alexey V
dc.contributor.authorYao, Zhi
dc.contributor.authorLittle, Daniel
dc.contributor.authorBanushi, Blerida
dc.contributor.authorAl-Menhali, Afnan Saleh
dc.contributor.authorRanasinghe, Rohan
dc.contributor.authorWhiten, Daniel
dc.contributor.authorYapom, Ratsuda
dc.contributor.authorDolt, Karamjit Singh
dc.contributor.authorDevine, Michael J
dc.contributor.authorGissen, Paul
dc.contributor.authorKunath, Tilo
dc.contributor.authorJaganjac, Morana
dc.contributor.authorPavlov, Evgeny V
dc.contributor.authorKlenerman, David
dc.contributor.authorAbramov, Andrey Y
dc.contributor.authorGandhi, Sonia
dc.date.accessioned2018-10-10T17:30:29Z
dc.date.available2018-10-10T17:30:29Z
dc.date.issued2018-06-12
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283571
dc.description.abstractProtein aggregation causes α-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric α-synuclein improves ATP synthase efficiency. Here, we report that aggregation of monomers generates beta sheet-rich oligomers that localise to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric α-synuclein impairs complex I-dependent respiration. Oligomers induce selective oxidation of the ATP synthase beta subunit and mitochondrial lipid peroxidation. These oxidation events increase the probability of permeability transition pore (PTP) opening, triggering mitochondrial swelling, and ultimately cell death. Notably, inhibition of oligomer-induced oxidation prevents the pathological induction of PTP. Inducible pluripotent stem cells (iPSC)-derived neurons bearing SNCA triplication, generate α-synuclein aggregates that interact with the ATP synthase and induce PTP opening, leading to neuronal death. This study shows how the transition of α-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson's disease.
dc.format.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectNeurons
dc.subjectMitochondria
dc.subjectAnimals
dc.subjectHumans
dc.subjectRats
dc.subjectRats, Sprague-Dawley
dc.subjectParkinson Disease
dc.subjectReactive Oxygen Species
dc.subjectMitochondrial Proton-Translocating ATPases
dc.subjectMitochondrial Membrane Transport Proteins
dc.subjectCoculture Techniques
dc.subjectPatch-Clamp Techniques
dc.subjectProteomics
dc.subjectOxidation-Reduction
dc.subjectLipid Peroxidation
dc.subjectPermeability
dc.subjectalpha-Synuclein
dc.subjectEmbryonic Stem Cells
dc.subjectInduced Pluripotent Stem Cells
dc.subjectMitochondrial Permeability Transition Pore
dc.titleα-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease.
dc.typeArticle
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameNat Commun
prism.startingPage2293
prism.volume9
dc.identifier.doi10.17863/CAM.30933
dcterms.dateAccepted2018-04-20
rioxxterms.versionofrecord10.1038/s41467-018-04422-2
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-06-12
dc.contributor.orcidRanasinghe, Rohan [0000-0001-9227-4110]
dc.contributor.orcidWhiten, Daniel [0000-0002-7853-3566]
dc.contributor.orcidDevine, Michael J [0000-0001-6076-3382]
dc.contributor.orcidGissen, Paul [0000-0002-9712-6122]
dc.contributor.orcidKunath, Tilo [0000-0002-8805-7356]
dc.contributor.orcidKlenerman, David [0000-0001-7116-6954]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
cam.issuedOnline2018-06-12


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International