Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism.
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.
1 Lund University, Department of Clinical Sciences Lund, Neurology, Sweden Springer.Wolfdieter@mayo.edu Andreas.Puschmann@med.lu.se.|2 Department of Neurology, Skåne University Hospital, Sweden.|3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Andreas
A
Puschmann
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Fabienne C
FC
Fiesel
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Thomas R
TR
Caulfield
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Roman
R
Hudec
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Maya
M
Ando
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Dominika
D
Truban
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Xu
X
Hou
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Kotaro
K
Ogaki
4 Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL 32224, USA.
Michael G
MG
Heckman
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Elle D
ED
James
5 Lund University, Department of Experimental Medical Science, Lund, Sweden.
Maria
M
Swanberg
5 Lund University, Department of Experimental Medical Science, Lund, Sweden.
Itzia
I
Jimenez-Ferrer
6 Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sweden.|7 Memory Clinic, Skåne University Hospital, Malmö, Sweden.
Oskar
O
Hansson
8 Department of Neurology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
Grzegorz
G
Opala
8 Department of Neurology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
Joanna
J
Siuda
8 Department of Neurology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
Magdalena
M
Boczarska-Jedynak
9 Department of Neurology, Medical University of Warsaw, Poland.
Andrzej
A
Friedman
9 Department of Neurology, Medical University of Warsaw, Poland.
Dariusz
D
Koziorowski
Monika
M
Rudzińska-Bar
10 Department of Neurology, St. Olav's Hospital, and Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
Jan O
JO
Aasly
11 Dublin Neurological Institute at the Mater Misericordiae University Hospital, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Timothy
T
Lynch
12 Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
George D
GD
Mellick
12 Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
Megha
M
Mohan
12 Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.|13 University of Queensland, Asia-Pacific Centre for Neuromodulation, Centre for Clinical Research, Brisbane, Queensland, Australia.
Peter A
PA
Silburn
14 Lviv Regional Clinical Hospital, Lviv, Ukraine.
Yanosh
Y
Sanotsky
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.|15 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Carles
C
Vilariño-Güell
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.|15 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Matthew J
MJ
Farrer
16 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|17 Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|18 Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Li
L
Chen
16 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|17 Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|18 Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.|19 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|20 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Valina L
VL
Dawson
16 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|17 Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|18 Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.|19 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|21 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ted M
TM
Dawson
22 Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
Zbigniew K
ZK
Wszolek
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.|23 School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.|24 Mayo Graduate School, Neurobiology of Disease, Mayo Clinic, Jacksonville, FL 32224, USA.
Owen A
OA
Ross
3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA Springer.Wolfdieter@mayo.edu Andreas.Puschmann@med.lu.se.|24 Mayo Graduate School, Neurobiology of Disease, Mayo Clinic, Jacksonville, FL 32224, USA.
Wolfdieter
W
Springer
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D005347:Fibroblasts; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*; D012306:Risk; D055815:Young Adult; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase
PINK1; Parkinson’s disease; heterozygous mutation; mitophagy; ubiquitin