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dc.contributor.authorJonikas, Mindaugas
dc.contributor.authorMadill, Martin
dc.contributor.authorMathy, Alexandre
dc.contributor.authorZekoll, Theresa
dc.contributor.authorZois, Christos E
dc.contributor.authorWigfield, Simon
dc.contributor.authorKurzawa-Akanbi, Marzena
dc.contributor.authorBrowne, Cathy
dc.contributor.authorSims, David
dc.contributor.authorChinnery, Patrick F
dc.contributor.authorCowley, Sally A
dc.contributor.authorTofaris, George K
dc.date.accessioned2018-11-05T10:25:57Z
dc.date.available2018-11-05T10:25:57Z
dc.date.issued2018-05
dc.identifier.issn0364-5134
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284605
dc.description.abstractOBJECTIVE: Defective mitochondrial function attributed to optic atrophy 1 (OPA1) mutations causes primarily optic atrophy and, less commonly, neurodegenerative syndromes. The pathomechanism by which OPA1 mutations trigger diffuse loss of neurons in some, but not all, patients is unknown. Here, we used a tractable induced pluripotent stem cell (iPSC)-based model to capture the biology of OPA1 haploinsufficiency in cases presenting with classic eye disease versus syndromic parkinsonism. METHODS: iPSCs were generated from 2 patients with OPA1 haploinsufficiency and 2 controls and differentiated into dopaminergic neurons. Metabolic profile was determined by extracellular flux analysis, respiratory complex levels using immunoblotting, and complex I activity by a colorimetric assay. Mitochondria were examined by transmission electron microscopy. Mitochondrial DNA copy number and deletions were assayed using long-range PCR. Mitochondrial membrane potential was measured by tetramethylrhodamine methyl ester uptake, and mitochondrial fragmentation was assessed by confocal microscopy. Exome sequencing was used to screen for pathogenic variants. RESULTS: OPA1 haploinsufficient iPSCs differentiated into dopaminergic neurons and exhibited marked reduction in OPA1 protein levels. Loss of OPA1 caused a late defect in oxidative phosphorylation, reduced complex I levels, and activity without a significant change in the ultrastructure of mitochondria. Loss of neurons in culture recapitulated dopaminergic degeneration in syndromic disease and correlated with mitochondrial fragmentation. INTERPRETATION: OPA1 levels maintain oxidative phosphorylation in iPSC-derived neurons, at least in part, by regulating the stability of complex I. Severity of OPA1 disease associates primarily with the extent of OPA1-mediated fusion, suggesting that activation of this mechanism or identification of its genetic modifiers may have therapeutic or prognostic value. Ann Neurol 2018;83:915-925.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherWiley
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMitochondria
dc.subjectHumans
dc.subjectParkinsonian Disorders
dc.subjectOptic Atrophy
dc.subjectGTP Phosphohydrolases
dc.subjectDNA, Mitochondrial
dc.subjectOxidative Phosphorylation
dc.subjectMembrane Potential, Mitochondrial
dc.subjectInduced Pluripotent Stem Cells
dc.titleStem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1.
dc.typeArticle
prism.endingPage925
prism.issueIdentifier5
prism.publicationDate2018
prism.publicationNameAnn Neurol
prism.startingPage915
prism.volume83
dc.identifier.doi10.17863/CAM.31979
dcterms.dateAccepted2018-03-23
rioxxterms.versionofrecord10.1002/ana.25221
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-05
dc.contributor.orcidTofaris, George K [0000-0002-9252-5933]
dc.identifier.eissn1531-8249
rioxxterms.typeJournal Article/Review
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (unknown)
pubs.funder-project-idWellcome Trust (101876/Z/13/Z)
pubs.funder-project-idWellcome Trust (101876/B/13/A)
pubs.funder-project-idDepartment of Health (via Newcastle University) (BH091682-RG81903)
pubs.funder-project-idMedical Research Council (MR/M024962/1)
pubs.funder-project-idMedical Research Council (MR/L023784/1)
cam.issuedOnline2018-04-25


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