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Brain. 2017 Jan;140(1):98-117. doi: 10.1093/brain/aww261. Epub 2016 Nov 2.

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

Author information

1
1 Lund University, Department of Clinical Sciences Lund, Neurology, Sweden Springer.Wolfdieter@mayo.edu Andreas.Puschmann@med.lu.se.
2
2 Department of Neurology, Skåne University Hospital, Sweden.
3
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
4
4 Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL 32224, USA.
5
5 Lund University, Department of Experimental Medical Science, Lund, Sweden.
6
6 Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sweden.
7
7 Memory Clinic, Skåne University Hospital, Malmö, Sweden.
8
8 Department of Neurology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
9
9 Department of Neurology, Medical University of Warsaw, Poland.
10
10 Department of Neurology, St. Olav's Hospital, and Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
11
11 Dublin Neurological Institute at the Mater Misericordiae University Hospital, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
12
12 Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
13
13 University of Queensland, Asia-Pacific Centre for Neuromodulation, Centre for Clinical Research, Brisbane, Queensland, Australia.
14
14 Lviv Regional Clinical Hospital, Lviv, Ukraine.
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15 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
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16 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
17
17 Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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18 Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
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19 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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20 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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21 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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22 Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
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23 School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
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24 Mayo Graduate School, Neurobiology of Disease, Mayo Clinic, Jacksonville, FL 32224, USA.
25
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA Springer.Wolfdieter@mayo.edu Andreas.Puschmann@med.lu.se.

Erratum in

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:

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

PMID:
27807026
PMCID:
PMC5379862
DOI:
10.1093/brain/aww261
[Indexed for MEDLINE]
Free PMC Article

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