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

Andreas Puschmann, Fabienne Fiesel, Thomas Caulfield, Roman Hudec, Maya Ando, Dominika Truban, Xu Hou, Kotaro Ogaki, Michael G. Heckman, Elle D. James, Maria Swanberg, Itzia Jimenez-Ferrer, Oskar Hansson, Grzegorz Opala, Joanna Siuda, Magdalena Boczarska-Jedynak, Andrzej Friedman, Dariusz Koziorowski, Jan O. Aasly, Timothy LynchGeorge D. Mellick, Megha Mohan, Peter A. Silburn, Yanosh Sanotsky, Carles Vilariño-Güell, Matthew J. Farrer, Li Chen, Valina L. Dawson, Ted M. Dawson, Zbigniew K. Wszolek, Zbigniew K Wszolek, Owen A Ross

Research output: Contribution to journalArticle

47 Citations (Scopus)

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 = 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.

Original languageEnglish (US)
Pages (from-to)98-117
Number of pages20
JournalBrain : a journal of neurology
Volume140
DOIs
StatePublished - Jan 1 2017

Fingerprint

Parkinson Disease
Heterozygote
Mutation
Odds Ratio
PTEN-induced putative kinase
Parkinson's Disease
Phosphotransferases
Recessive Genes
Inheritance Patterns
Genetic Association Studies
Molecular Dynamics Simulation
Ubiquitin
Quality Control
Proteins
Fibroblasts
Alleles
Phosphorylation
Protein
Phenotype
Neurons

Keywords

  • heterozygous mutation
  • mitophagy
  • Parkinson’s disease
  • PINK1
  • ubiquitin

ASJC Scopus subject areas

  • Medicine(all)
  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism. / Puschmann, Andreas; Fiesel, Fabienne; Caulfield, Thomas; Hudec, Roman; Ando, Maya; Truban, Dominika; Hou, Xu; Ogaki, Kotaro; Heckman, Michael G.; James, Elle D.; Swanberg, Maria; Jimenez-Ferrer, Itzia; Hansson, Oskar; Opala, Grzegorz; Siuda, Joanna; Boczarska-Jedynak, Magdalena; Friedman, Andrzej; Koziorowski, Dariusz; Aasly, Jan O.; Lynch, Timothy; Mellick, George D.; Mohan, Megha; Silburn, Peter A.; Sanotsky, Yanosh; Vilariño-Güell, Carles; Farrer, Matthew J.; Chen, Li; Dawson, Valina L.; Dawson, Ted M.; Wszolek, Zbigniew K.; Wszolek, Zbigniew K; Ross, Owen A.

In: Brain : a journal of neurology, Vol. 140, 01.01.2017, p. 98-117.

Research output: Contribution to journalArticle

Puschmann, A, Fiesel, F, Caulfield, T, Hudec, R, Ando, M, Truban, D, Hou, X, Ogaki, K, Heckman, MG, James, ED, Swanberg, M, Jimenez-Ferrer, I, Hansson, O, Opala, G, Siuda, J, Boczarska-Jedynak, M, Friedman, A, Koziorowski, D, Aasly, JO, Lynch, T, Mellick, GD, Mohan, M, Silburn, PA, Sanotsky, Y, Vilariño-Güell, C, Farrer, MJ, Chen, L, Dawson, VL, Dawson, TM, Wszolek, ZK, Wszolek, ZK & Ross, OA 2017, 'Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism', Brain : a journal of neurology, vol. 140, pp. 98-117. https://doi.org/10.1093/brain/aww261
Puschmann, Andreas ; Fiesel, Fabienne ; Caulfield, Thomas ; Hudec, Roman ; Ando, Maya ; Truban, Dominika ; Hou, Xu ; Ogaki, Kotaro ; Heckman, Michael G. ; James, Elle D. ; Swanberg, Maria ; Jimenez-Ferrer, Itzia ; Hansson, Oskar ; Opala, Grzegorz ; Siuda, Joanna ; Boczarska-Jedynak, Magdalena ; Friedman, Andrzej ; Koziorowski, Dariusz ; Aasly, Jan O. ; Lynch, Timothy ; Mellick, George D. ; Mohan, Megha ; Silburn, Peter A. ; Sanotsky, Yanosh ; Vilariño-Güell, Carles ; Farrer, Matthew J. ; Chen, Li ; Dawson, Valina L. ; Dawson, Ted M. ; Wszolek, Zbigniew K. ; Wszolek, Zbigniew K ; Ross, Owen A. / Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism. In: Brain : a journal of neurology. 2017 ; Vol. 140. pp. 98-117.
@article{98a01648c4814da9b299a61d34cd4366,
title = "Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism",
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 = 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.",
keywords = "heterozygous mutation, mitophagy, Parkinson’s disease, PINK1, ubiquitin",
author = "Andreas Puschmann and Fabienne Fiesel and Thomas Caulfield and Roman Hudec and Maya Ando and Dominika Truban and Xu Hou and Kotaro Ogaki and Heckman, {Michael G.} and James, {Elle D.} and Maria Swanberg and Itzia Jimenez-Ferrer and Oskar Hansson and Grzegorz Opala and Joanna Siuda and Magdalena Boczarska-Jedynak and Andrzej Friedman and Dariusz Koziorowski and Aasly, {Jan O.} and Timothy Lynch and Mellick, {George D.} and Megha Mohan and Silburn, {Peter A.} and Yanosh Sanotsky and Carles Vilari{\~n}o-G{\"u}ell and Farrer, {Matthew J.} and Li Chen and Dawson, {Valina L.} and Dawson, {Ted M.} and Wszolek, {Zbigniew K.} and Wszolek, {Zbigniew K} and Ross, {Owen A}",
year = "2017",
month = "1",
day = "1",
doi = "10.1093/brain/aww261",
language = "English (US)",
volume = "140",
pages = "98--117",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",

}

TY - JOUR

T1 - Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism

AU - Puschmann, Andreas

AU - Fiesel, Fabienne

AU - Caulfield, Thomas

AU - Hudec, Roman

AU - Ando, Maya

AU - Truban, Dominika

AU - Hou, Xu

AU - Ogaki, Kotaro

AU - Heckman, Michael G.

AU - James, Elle D.

AU - Swanberg, Maria

AU - Jimenez-Ferrer, Itzia

AU - Hansson, Oskar

AU - Opala, Grzegorz

AU - Siuda, Joanna

AU - Boczarska-Jedynak, Magdalena

AU - Friedman, Andrzej

AU - Koziorowski, Dariusz

AU - Aasly, Jan O.

AU - Lynch, Timothy

AU - Mellick, George D.

AU - Mohan, Megha

AU - Silburn, Peter A.

AU - Sanotsky, Yanosh

AU - Vilariño-Güell, Carles

AU - Farrer, Matthew J.

AU - Chen, Li

AU - Dawson, Valina L.

AU - Dawson, Ted M.

AU - Wszolek, Zbigniew K.

AU - Wszolek, Zbigniew K

AU - Ross, Owen A

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - heterozygous mutation

KW - mitophagy

KW - Parkinson’s disease

KW - PINK1

KW - ubiquitin

UR - http://www.scopus.com/inward/record.url?scp=85018383742&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018383742&partnerID=8YFLogxK

U2 - 10.1093/brain/aww261

DO - 10.1093/brain/aww261

M3 - Article

C2 - 27807026

AN - SCOPUS:85018383742

VL - 140

SP - 98

EP - 117

JO - Brain

JF - Brain

SN - 0006-8950

ER -