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, Monika Rudzińska-Bar, Jan O. AaslyTimothy Lynch, George 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, Owen A. Ross, Wolfdieter Springer

Research output: Contribution to journalArticle

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Abstract

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.1231G4A, 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
Volume140
Issue number1
DOIs
StatePublished - Jan 1 2017

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Keywords

  • Heterozygous mutation
  • Mitophagy
  • PINK1
  • Parkinson's disease
  • Ubiquitin

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Puschmann, A., Fiesel, F. C., Caulfield, T. R., Hudec, R., Ando, M., Truban, D., Hou, X., Ogaki, K., Heckman, M. G., James, E. D., Swanberg, M., Jimenez-Ferrer, I., Hansson, O., Opala, G., Siuda, J., Boczarska-Jedynak, M., Friedman, A., Koziorowski, D., Rudzińska-Bar, M., ... Springer, W. (2017). Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism. Brain, 140(1), 98-117. https://doi.org/10.1093/brain/aww261