학술논문
Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism
Document Type
Author
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 Carrillo, 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, Ted M.; Wszolek, Zbigniew K; Ross, Owen A.; Springer, Wolfdieter
Source
Brain MultiPark: Multidisciplinary research focused on Parkinson´s disease. 140(1):98-117
Subject
Language
English
ISSN
1460-2156
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.