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dc.contributor.authorBrunetti, Darioen
dc.contributor.authorTorsvik, Jannicheen
dc.contributor.authorDallabona, Cristinaen
dc.contributor.authorTeixeira, Pedroen
dc.contributor.authorSztromwasser, Pawelen
dc.contributor.authorFernandez-Vizarra, Erikaen
dc.contributor.authorCerutti, Raffaeleen
dc.contributor.authorReyes Tellez, Aurelioen
dc.contributor.authorPreziuso, Carmelaen
dc.contributor.authorD'Amati, Giuliaen
dc.contributor.authorBaruffini, Enricoen
dc.contributor.authorGoffrini, Paolaen
dc.contributor.authorViscomi, Carloen
dc.contributor.authorFerrero, Ileanaen
dc.contributor.authorBoman, Helgeen
dc.contributor.authorTelstad, Wencheen
dc.contributor.authorJohansson, Stefanen
dc.contributor.authorGlaser, Elzbietaen
dc.contributor.authorKnappskog, Per Men
dc.contributor.authorZeviani, Massimoen
dc.contributor.authorBindoff, Laurence Aen
dc.date.accessioned2017-08-11T10:30:19Z
dc.date.available2017-08-11T10:30:19Z
dc.date.issued2016-03-01en
dc.identifier.issn1757-4676
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/266260
dc.description.abstractMitochondrial dysfunction and altered proteostasis are central features of neurodegenerative diseases. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests oligopeptides, including the mitochondrial targeting sequences that are cleaved from proteins imported across the inner mitochondrial membrane and the mitochondrial fraction of amyloid beta (Aβ). We identified two siblings carrying a homozygous PITRM1 missense mutation (c.548G>A, p.Arg183Gln) associated with an autosomal recessive, slowly progressive syndrome characterised by mental retardation, spinocerebellar ataxia, cognitive decline and psychosis. The pathogenicity of the mutation was tested in vitro, in mutant fibroblasts and skeletal muscle, and in a yeast model. A Pitrm1(+/-) heterozygous mouse showed progressive ataxia associated with brain degenerative lesions, including accumulation of Aβ-positive amyloid deposits. Our results show that PITRM1 is responsible for significant Aβ degradation and that impairment of its activity results in Aβ accumulation, thus providing a mechanistic demonstration of the mitochondrial involvement in amyloidotic neurodegeneration.
dc.description.sponsorshipCariplo2011‐0526 ERCFP7‐322424 Swedish Research Council Helse Vest911810 Forening for muskelsyke Italian Ministry of HealthGR‐2010‐2306‐756
dc.languageengen
dc.language.isoenen
dc.publisherWiley
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectamyloid betaen
dc.subjectmitochondrial diseaseen
dc.subjectmitochondrial targeting sequenceen
dc.subjectneurodegenerationen
dc.subjectpitrilysin 1en
dc.subjectAmyloid beta-Peptidesen
dc.subjectAnimalsen
dc.subjectBrainen
dc.subjectDisease Models, Animalen
dc.subjectHistocytochemistryen
dc.subjectHumansen
dc.subjectMagnetic Resonance Imagingen
dc.subjectMetalloendopeptidasesen
dc.subjectMiceen
dc.subjectModels, Biologicalen
dc.subjectMuscle, Skeletalen
dc.subjectMutant Proteinsen
dc.subjectMutation, Missenseen
dc.subjectNeurodegenerative Diseasesen
dc.subjectSaccharomyces cerevisiaeen
dc.subjectSiblingsen
dc.titleDefective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration.en
dc.typeArticle
prism.endingPage190
prism.issueIdentifier3en
prism.publicationDate2016en
prism.publicationNameEMBO Molecular Medicineen
prism.startingPage176
prism.volume8en
dc.identifier.doi10.17863/CAM.10002
dcterms.dateAccepted2015-11-23en
rioxxterms.versionofrecord10.15252/emmm.201505894en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2016-03-01en
dc.contributor.orcidReyes Tellez, Aurelio [0000-0003-2876-2202]
dc.contributor.orcidViscomi, Carlo [0000-0001-6050-0566]
dc.identifier.eissn1757-4684
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idEuropean Commission FP7 ERC Advanced Investigator Grants (AIG) (322424)
pubs.funder-project-idMRC (MC_UP_1002/1)
cam.issuedOnline2015-12-23en
dc.identifier.urlhttp://embomolmed.embopress.org/content/8/3/176en


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