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Heteroplasmic mitochondrial DNA mutations in frontotemporal lobar degeneration.

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cam.issuedOnline2022-04-30
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 F
dc.contributor.orcidChinnery, Patrick F [0000-0002-7065-6617]
dc.date.accessioned2022-06-07T08:13:50Z
dc.date.available2022-06-07T08:13:50Z
dc.date.issued2022-06
dc.date.updated2022-06-07T08:13:49Z
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.identifier.doi10.17863/CAM.85210
dc.identifier.eissn1432-0533
dc.identifier.issn0001-6322
dc.identifier.other35488929
dc.identifier.otherPMC9107417
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337801
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1007/s00401-022-02423-6
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 0412041
dc.sourceessn: 1432-0533
dc.subjectDNA, Mitochondrial
dc.subjectFrontotemporal Dementia
dc.subjectFrontotemporal Lobar Degeneration
dc.subjectHeteroplasmy
dc.subjectHumans
dc.subjectMutation
dc.titleHeteroplasmic mitochondrial DNA mutations in frontotemporal lobar degeneration.
dc.typeArticle
dcterms.dateAccepted2022-04-18
prism.endingPage695
prism.issueIdentifier6
prism.publicationNameActa Neuropathol
prism.startingPage687
prism.volume143
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 and Care Research (IS-BRC-1215-20014)
pubs.funder-project-idMedical Research Council (MC_UU_00005/12)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/N01426X/1)
pubs.funder-project-idMedical Research Council (MC_UU_00015/7)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1007/s00401-022-02423-6

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