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Heterozygous PINK1 ...
Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism
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- Puschmann, Andreas (författare)
- Lund 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
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- Fiesel, Fabienne C (författare)
- Mayo Clinic Florida
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- Caulfield, Thomas R (författare)
- Mayo Clinic Florida
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- Hudec, Roman (författare)
- Mayo Clinic Florida
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- Ando, Maya (författare)
- Mayo Clinic Florida
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- Truban, Dominika (författare)
- Mayo Clinic Florida
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- Hou, Xu (författare)
- Mayo Clinic Florida
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- Ogaki, Kotaro (författare)
- Mayo Clinic Florida
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- Heckman, Michael G. (författare)
- Mayo Clinic Florida
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- James, Elle D (författare)
- Mayo Clinic Florida
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- Swanberg, Maria (författare)
- Lund University,Lunds universitet,Translationell Neurogenetik,Forskargrupper vid Lunds universitet,Translational Neurogenetics,Lund University Research Groups
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- Jimenez Ferrer Carrillo, Itzia (författare)
- Lund University,Lunds universitet,Translationell Neurogenetik,Forskargrupper vid Lunds universitet,Translational Neurogenetics,Lund University Research Groups
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- Hansson, Oskar (författare)
- Lund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Clinical Memory Research,Lund University Research Groups,Skåne University Hospital
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- Opala, Grzegorz (författare)
- Medical University of Silesia
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- Siuda, Joanna (författare)
- Medical University of Silesia
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- Boczarska-Jedynak, Magdalena (författare)
- Medical University of Silesia
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- Friedman, Andrzej (författare)
- Medical University of Warsaw
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Koziorowski, Dariusz (författare)
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- Aasly, Jan O. (författare)
- Norwegian University of Science and Technology
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- Lynch, Timothy (författare)
- University College Dublin
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- Mellick, George D. (författare)
- Griffith University
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- Mohan, Megha (författare)
- Griffith University
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- Silburn, Peter A. (författare)
- University of Queensland
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- Sanotsky, Yanosh (författare)
- Lviv Regional Clinical Hospital
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- Vilariño-Güell, Carles (författare)
- University of British Columbia
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- Farrer, Matthew J. (författare)
- University of British Columbia
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- Chen, Li (författare)
- Adrienne Helis Malvin Medical Research Foundation
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- Dawson, Valina L (författare)
- Johns Hopkins University School of Medicine
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- Dawson, Ted M. (författare)
- Johns Hopkins University School of Medicine
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- Wszolek, Zbigniew K (författare)
- Mayo Clinic Florida
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- Ross, Owen A. (författare)
- Mayo Clinic Florida
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- Springer, Wolfdieter (författare)
- Mayo Clinic Florida
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(creator_code:org_t)
- 2016-11-02
- 2017
- Engelska.
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 140:1, s. 98-117
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://academic.oup...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
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- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
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- Journal Article
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Puschmann, Andre ...
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Fiesel, Fabienne ...
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Caulfield, Thoma ...
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Hudec, Roman
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Ando, Maya
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Truban, Dominika
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visa fler...
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Hou, Xu
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Ogaki, Kotaro
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Heckman, Michael ...
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James, Elle D
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Swanberg, Maria
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Jimenez Ferrer C ...
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Hansson, Oskar
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Opala, Grzegorz
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Siuda, Joanna
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Boczarska-Jedyna ...
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Friedman, Andrze ...
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Koziorowski, Dar ...
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Aasly, Jan O.
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Lynch, Timothy
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Mellick, George ...
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Mohan, Megha
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Silburn, Peter A ...
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Sanotsky, Yanosh
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Vilariño-Güell, ...
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Farrer, Matthew ...
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Chen, Li
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Dawson, Valina L
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Dawson, Ted M.
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Wszolek, Zbignie ...
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Ross, Owen A.
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Springer, Wolfdi ...
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