TY - JOUR
T1 - Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism
AU - Puschmann, Andreas
AU - Fiesel, Fabienne C.
AU - Caulfield, Thomas R.
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 - Rudzińska-Bar, Monika
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 - Ross, Owen A.
AU - Springer, Wolfdieter
N1 - Publisher Copyright:
© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2017/1
Y1 - 2017/1
N2 - 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.
AB - 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.
KW - Heterozygous mutation
KW - Mitophagy
KW - PINK1
KW - Parkinson's disease
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
SN - 0006-8950
VL - 140
SP - 98
EP - 117
JO - Brain
JF - Brain
IS - 1
ER -