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  • Puschmann, AndreasLund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Klinisk neurogenetik,Forskargrupper vid Lunds universitet,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Clinical Neurogenetics,Lund University Research Groups,Skåne University Hospital,Mayo Clinic Florida (author)

Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism

  • Article/chapterEnglish2017

Publisher, publication year, extent ...

  • 2016-11-02
  • Oxford University Press (OUP),2017

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  • LIBRIS-ID:oai:lup.lub.lu.se:951e000a-d661-45e6-b046-dedac7c44f41
  • https://lup.lub.lu.se/record/951e000a-d661-45e6-b046-dedac7c44f41URI
  • https://doi.org/10.1093/brain/aww261DOI

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  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It 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.

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  • Fiesel, Fabienne CMayo Clinic Florida (author)
  • Caulfield, Thomas RMayo Clinic Florida (author)
  • Hudec, RomanMayo Clinic Florida (author)
  • Ando, MayaMayo Clinic Florida (author)
  • Truban, DominikaMayo Clinic Florida (author)
  • Hou, XuMayo Clinic Florida (author)
  • Ogaki, KotaroMayo Clinic Florida (author)
  • Heckman, Michael G.Mayo Clinic Florida (author)
  • James, Elle DMayo Clinic Florida (author)
  • Swanberg, MariaLund University,Lunds universitet,Translationell Neurogenetik,Forskargrupper vid Lunds universitet,Translational Neurogenetics,Lund University Research Groups(Swepub:lu)med-msr (author)
  • Jimenez Ferrer Carrillo, ItziaLund University,Lunds universitet,Translationell Neurogenetik,Forskargrupper vid Lunds universitet,Translational Neurogenetics,Lund University Research Groups(Swepub:lu)med-iaj (author)
  • Hansson, OskarLund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Clinical Memory Research,Lund University Research Groups,Skåne University Hospital(Swepub:lu)mphy-ohn (author)
  • Opala, GrzegorzMedical University of Silesia (author)
  • Siuda, JoannaMedical University of Silesia (author)
  • Boczarska-Jedynak, MagdalenaMedical University of Silesia (author)
  • Friedman, AndrzejMedical University of Warsaw (author)
  • Koziorowski, Dariusz (author)
  • Aasly, Jan O.Norwegian University of Science and Technology (author)
  • Lynch, TimothyUniversity College Dublin (author)
  • Mellick, George D.Griffith University (author)
  • Mohan, MeghaGriffith University (author)
  • Silburn, Peter A.University of Queensland (author)
  • Sanotsky, YanoshLviv Regional Clinical Hospital (author)
  • Vilariño-Güell, CarlesUniversity of British Columbia (author)
  • Farrer, Matthew J.University of British Columbia (author)
  • Chen, LiAdrienne Helis Malvin Medical Research Foundation (author)
  • Dawson, Valina LJohns Hopkins University School of Medicine (author)
  • Dawson, Ted M.Johns Hopkins University School of Medicine (author)
  • Wszolek, Zbigniew KMayo Clinic Florida (author)
  • Ross, Owen A.Mayo Clinic Florida (author)
  • Springer, WolfdieterMayo Clinic Florida (author)
  • Neurologi, LundSektion IV (creator_code:org_t)

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  • In:Brain: Oxford University Press (OUP)140:1, s. 98-1171460-21560006-8950

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