Journal
BRAIN
Volume 140, Issue -, Pages 98-117Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/aww261
Keywords
Parkinson's disease; PINK1; heterozygous mutation; ubiquitin; mitophagy
Categories
Funding
- Swedish Parkinson Academy
- Swedish Parkinson Foundation (Parkinsonfonden)
- Swedish National Health Services (ALF)
- Bundy Academy, Lund, Sweden
- National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) [NS085070]
- Michael J. Fox Foundation for Parkinson's Research
- Foundation for Mitochondrial Medicine
- Mayo Clinic Center for Regenerative Medicine (CRM)
- Center for Individualized Medicine (CIM)
- Center for Biomedical Discovery (CBD)
- Marriott Family Foundation
- Gerstner Family Career Development Award
- American Parkinson Disease Association (APDA)
- Uehara Memorial Foundation
- NIH/NINDS [NS078086, NS38377, MDSCRF 2007-MSCRFI-0420-00, 2009-MSCRFII-0125-00, MDSCRF 2012-MSCRFII-0268-00, MDSCRF 2013-MSCRFII-0105-00]
- Mayo Clinic Center for Individualized Medicine (CIM)
- Mayo Clinic Florida Neuroscience Focused Research Team Awards
- European Research Council
- Swedish Research Council
- Swedish Brain Power
- ALF
- NHMRC [APP1084560]
- CONCYT PhD program
- MultiPark, Lund University, Sweden
- JPB Foundation
- Foundation's Parkinson's Disease Program [M-1]
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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.
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