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

Andreas Puschmann, Fabienne C. Fiesel, Thomas R. 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, Valina Dawson, Ted M Dawson, Owen A. Ross, Wolfdieter Springer

Research output: Contribution to journalArticle

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

Puschmann, A., Fiesel, F. C., Caulfield, T. R., Hudec, R., Ando, M., Truban, D., ... Springer, W. (2017). Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism. Brain : a journal of neurology, 140, 98-117. https://doi.org/10.1093/brain/aww261

Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism. / Puschmann, Andreas; Fiesel, Fabienne C.; Caulfield, Thomas R.; 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, Valina; Dawson, Ted M; Ross, Owen A.; Springer, Wolfdieter.

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

Research output: Contribution to journalArticle

Puschmann, A, Fiesel, FC, Caulfield, TR, 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, V, Dawson, TM, Ross, OA & Springer, W 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 C. ; Caulfield, Thomas R. ; 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, Valina ; Dawson, Ted M ; Ross, Owen A. ; Springer, Wolfdieter. / 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.
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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.",
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T1 - Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism

AU - Puschmann, Andreas

AU - Fiesel, Fabienne C.

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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, Valina

AU - Dawson, Ted M

AU - Ross, Owen A.

AU - Springer, Wolfdieter

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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

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