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

• Published in: Brain (London, England : 1878) Vol. 140; no. 1; pp. 98 - 117
• Main Authors: 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, 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.01.2017
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Basic Medicine; Case-Control Studies; Clinical Medicine; Female; Fibroblasts; Genetic Association Studies; Genetic Predisposition to Disease - genetics; Heterozygote; Humans; Klinisk medicin; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Middle Aged; Models, Molecular; Neurologi; Neurology; Neurosciences; Neurovetenskaper; Original; Parkinson Disease - genetics; Pedigree; Protein Kinases - genetics; Risk; Young Adult; heterozygous mutation; PINK1; mitophagy; Parkinson’s disease; ubiquitin
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/aww261

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.