Show simple item record

dc.contributor.authorPuschmann, Andreasen_US
dc.contributor.authorFiesel, Fabienne C.en_US
dc.contributor.authorCaulfield, Thomas R.en_US
dc.contributor.authorHudec, Romanen_US
dc.contributor.authorAndo, Mayaen_US
dc.contributor.authorTruban, Dominikaen_US
dc.contributor.authorHou, Xuen_US
dc.contributor.authorOgaki, Kotaroen_US
dc.contributor.authorHeckman, Michael G.en_US
dc.contributor.authorJames, Elle D.en_US
dc.contributor.authorSwanberg, Mariaen_US
dc.contributor.authorJimenez-Ferrer, Itziaen_US
dc.contributor.authorHansson, Oskaren_US
dc.contributor.authorOpala, Grzegorzen_US
dc.contributor.authorSiuda, Joannaen_US
dc.contributor.authorBoczarska-Jedynak, Magdalenaen_US
dc.contributor.authorFriedman, Andrzejen_US
dc.contributor.authorKoziorowski, Dariuszen_US
dc.contributor.authorAasly, Jan O.en_US
dc.contributor.authorLynch, Timothyen_US
dc.contributor.authorMellick, Georgeen_US
dc.contributor.authorMohan, Meghaen_US
dc.contributor.authorSilburn, Peteren_US
dc.contributor.authorSanotsky, Yanoshen_US
dc.contributor.authorVilarino-Guell, Carlesen_US
dc.contributor.authorFarrer, Matthew J.en_US
dc.contributor.authorChen, Lien_US
dc.contributor.authorDawson, Valina L.en_US
dc.contributor.authorDawson, Ted M.en_US
dc.contributor.authoret al.en_US
dc.date.accessioned2017-08-31T12:30:40Z
dc.date.available2017-08-31T12:30:40Z
dc.date.issued2016en_US
dc.identifier.issn0006-8950en_US
dc.identifier.doi10.1093/brain/aww261en_US
dc.identifier.urihttp://hdl.handle.net/10072/100614
dc.description.abstractIt has been postulated that heterozygous mutations in recessive Parkinson’s genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson’s disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson’s disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson’s disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.en_US
dc.description.peerreviewedYesen_US
dc.languageEnglishen_US
dc.publisherOxford University Pressen_US
dc.relation.ispartofpagefrom1en_US
dc.relation.ispartofpageto20en_US
dc.relation.ispartofjournalBrainen_US
dc.subject.fieldofresearchGenome Structure and Regulationen_US
dc.subject.fieldofresearchSystems Biologyen_US
dc.subject.fieldofresearchcode060407en_US
dc.subject.fieldofresearchcode060114en_US
dc.titleHeterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanismen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
dcterms.licensehttp://creativecommons.org/licenses/by-nc/4.0/en_US
dc.description.versionPublisheden_US
gro.rights.copyright© The Author(s) 2016. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comen_US
gro.hasfulltextFull Text


Files in this item

This item appears in the following Collection(s)

  • Journal articles
    Contains articles published by Griffith authors in scholarly journals.

Show simple item record