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

Puschmann, Andreas LU orcid ; Fiesel, Fabienne C ; Caulfield, Thomas R ; Hudec, Roman ; Ando, Maya ; Truban, Dominika ; Hou, Xu ; Ogaki, Kotaro ; Heckman, Michael G. and James, Elle D , et al. (2017) In Brain 140(1). p.98-117
Abstract

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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Journal Article
in
Brain
volume
140
issue
1
pages
98 - 117
publisher
Oxford University Press
external identifiers
  • scopus:85018383742
  • wos:000392710500018
  • pmid:27807026
ISSN
1460-2156
DOI
10.1093/brain/aww261
language
English
LU publication?
yes
id
951e000a-d661-45e6-b046-dedac7c44f41
date added to LUP
2017-02-20 14:00:45
date last changed
2024-04-14 05:55:04
@article{951e000a-d661-45e6-b046-dedac7c44f41,
  abstract     = {{<p>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&gt;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.</p>}},
  author       = {{Puschmann, Andreas and Fiesel, Fabienne C and Caulfield, Thomas R and Hudec, Roman and Ando, Maya and Truban, Dominika and Hou, Xu and Ogaki, Kotaro and Heckman, Michael G. and James, Elle D and Swanberg, Maria and Jimenez Ferrer Carrillo, Itzia and Hansson, Oskar and Opala, Grzegorz and Siuda, Joanna and Boczarska-Jedynak, Magdalena and Friedman, Andrzej and Koziorowski, Dariusz and Aasly, Jan O. and Lynch, Timothy and Mellick, George D. and Mohan, Megha and Silburn, Peter A. and Sanotsky, Yanosh and Vilariño-Güell, Carles and Farrer, Matthew J. and Chen, Li and Dawson, Valina L and Dawson, Ted M. and Wszolek, Zbigniew K and Ross, Owen A. and Springer, Wolfdieter}},
  issn         = {{1460-2156}},
  keywords     = {{Journal Article}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{98--117}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain}},
  title        = {{Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism}},
  url          = {{http://dx.doi.org/10.1093/brain/aww261}},
  doi          = {{10.1093/brain/aww261}},
  volume       = {{140}},
  year         = {{2017}},
}