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dc.contributor.authorNie, Yu
dc.contributor.authorMurley, Alexander
dc.contributor.authorGolder, Zoe
dc.contributor.authorRowe, James B
dc.contributor.authorAllinson, Kieren
dc.contributor.authorChinnery, Patrick
dc.date.accessioned2022-05-14T15:00:15Z
dc.date.available2022-05-14T15:00:15Z
dc.date.issued2022-06
dc.date.submitted2022-01-24
dc.identifier.issn0001-6322
dc.identifier.others00401-022-02423-6
dc.identifier.other2423
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337165
dc.description.abstractFrontotemporal lobar degeneration (FTLD) is a common cause of young onset dementia and is characterised by focal neuropathology. The reasons for the regional neuronal vulnerability are not known. Mitochondrial mechanisms have been implicated in the pathogenesis of FTLD, raising the possibility that frontotemporal regional mutations of mitochondrial DNA (mtDNA) are contributory causes. Here we applied dual sequencing of the entire mtDNA at high depth to identify high-fidelity single nucleotide variants (mtSNVs) and mtDNA rearrangements in post mortem brain tissue of people affected by FTLD and age-matched controls. Both mtSNVs and mtDNA rearrangements were elevated in the temporal lobe, with the greatest burden seen in FTLD. mtSNVs found in multiple brain regions also reached a higher heteroplasmy levels in the temporal lobe. The temporal lobe of people with FTLD had a higher burden of ribosomal gene variants predicted to affect intra-mitochondrial protein synthesis, and a higher proportion of missense variants in genes coding for respiratory chain subunits. In conclusion, heteroplasmic mtDNA variants predicted to affect oxidative phosphorylation are enriched in FTLD temporal lobe, and thus may contribute to the regional vulnerability in pathogenesis.
dc.languageen
dc.publisherSpringer
dc.subjectOriginal Paper
dc.titleHeteroplasmic mitochondrial DNA mutations in frontotemporal lobar degeneration.
dc.typeArticle
dc.date.updated2022-05-14T15:00:15Z
prism.endingPage695
prism.issueIdentifier6
prism.publicationNameActa Neuropathol
prism.startingPage687
prism.volume143
dc.identifier.doi10.17863/CAM.84584
dcterms.dateAccepted2022-04-18
rioxxterms.versionofrecord10.1007/s00401-022-02423-6
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidMurley, Alexander [0000-0003-0813-0670]
dc.contributor.orcidChinnery, Patrick [0000-0002-7065-6617]
dc.identifier.eissn1432-0533
pubs.funder-project-idAddenbrooke's Charitable Trust (ACT) (25/16A)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idEvelyn Trust (17/08)
pubs.funder-project-idWBH Foundation (via Cambridge in America) (Unknown)
pubs.funder-project-idWellcome Trust (212219/Z/18/Z)
pubs.funder-project-idWellcome Trust (103838/Z/14/Z)
pubs.funder-project-idMRC (MR/S035699/1)
pubs.funder-project-idNational Institute for Health Research (NIHRDH-IS-BRC-1215-20014)


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