Single Mutation in Recessive Gene Increases Risk of Earlier Onset Parkinson’s Disease

Summary: Researchers have discovered a genetic mutation that could signify a risk for early onset of Parkinson’s disease.

Source: Mayo Clinic.

A collaboration of 32 researchers in seven countries, led by scientists at Mayo Clinic’s campus in Florida, has found a genetic mutation they say confers a risk for development of Parkinson’s disease earlier than usual.

The major study, published in Brain, is important because the risk comes from a single mutation in the PTEN-induced putative kinase 1 (PINK1) gene. Investigators had believed that this rare form of Parkinson’s developed only when a person inherited mutations in both PINK1 alleles (one from each parent).

“We know that if you have mutations in both copies of PINK1, age at onset of Parkinson’s will usually be younger than 45. This study showed that if a person inherited a specific mutation in just one PINK1 gene, the disease could develop at about age 55 or so. By contrast, the most common, nonfamilial forms of Parkinson’s develop at about age 65,” says the study’s senior investigator, Wolfdieter Springer, Ph.D., a neuroscientist at Mayo Clinic’s Florida campus.

Genetic studies had suggested that a single mutated PINK1 allele might confer an outsized risk of the developing the disease. It took a “very effective synergetic” effort of clinical, structural and cell biologists, along with geneticists and data from thousands of affected patients, to show how it led to earlier disease development, Dr. Springer says.

“It took a real international collaboration to solve this puzzle,” he says.

PINK1 works with another gene, PARKIN, to ensure that mitochondria in neurons remain healthy. The mitochondria are the cell’s power plants, and many brain disorders, including Parkinson’s, are characterized by disruption in energy production in neurons.

When functioning, proteins from both genes work together to ensure the safe disposal of damaged mitochondria from the cell. They do this by producing a protein marker that labels damaged mitochondria that need to be destroyed. This procedure is part of an elaborate “quality control” system for mitochondria.

“The mitochondria are like a cell’s nuclear power plant that provides fantastic energy when they are running well,” Dr. Springer says. “But, when something goes wrong, the result can be catastrophic for the brain cell, causing neurodegeneration.”

Mutations in both PINK1 alleles (or copies) or in both PARKIN alleles mean that the PINK1-PARKIN pathway cannot function, and damaged mitochondria accumulate in a neuron, leading to its death.

Image shows a dna strand.

Genetic studies had suggested that a single mutated PINK1 allele might confer an outsized risk of the developing the disease NeuroscienceNews.com image is for illustrative purposes only.

This study showed that a specific mutation (p.G411S) in one copy of PINK1 substantially impairs this same pathway by inhibiting the protein produced from other healthy PINK1 allele. “This rare mutation has an outsized effect, and the remaining levels of functional PINK1 protein are not enough to cope with damaged mitochondria,” Dr. Springer says.

The findings could have implications for other neurodegenerative disorders, many of which feature mitochondrial damage, he says.

The study had started with genetic findings when one of the lead authors, Andreas Puschmann, M.D., Ph.D., of the Department of Neurology, Skåne University Hospital, Sweden, was a visiting scientist at Mayo Clinic. Additional structural and cell biological data then provided the sought-after mechanism to explain the observed phenomenon.

About this genetics research article

In addition from scientists in the U.S. and Sweden, researchers from Poland, Norway, Ireland, Ukraine and Australia participated in the study.

Funding: Dr. Springer is partially supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke [R01 #NS085070], the Michael J. Fox Foundation for Parkinson’s Research, Foundation for Mitochondrial Medicine, Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Center for Biomedical Discovery, Marriott Family Foundation, and a Gerstner Family Career Development Award. Dr. Puschmann is partially supported by the Swedish Parkinson Academy, the Swedish Parkinson Foundation (Parkinsonfonden), governmental funding for clinical research within the Swedish National Health Services, and the Bundy Academy (Lund, Sweden).

Source: Kevin Punsky – Mayo Clinic
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism” by Andreas Puschmann, Fabienne C. Fiesel, Thomas R. Caulfield, Roman Hudec, Maya Ando, Dominika Truban, Xu Hou, Kotaro Ogaki, Michael G. Heckman, Elle D. James, Maria Swanberg, Itzia Jimenez-Ferrer, Oskar Hansson, Grzegorz Opala, Joanna Siuda, Magdalena Boczarska-Jedynak, Andrzej Friedman, Dariusz Koziorowski, Jan O. Aasly, Timothy Lynch, George D. Mellick, Megha Mohan, Peter A. Silburn, Yanosh Sanotsky, Carles Vilariño-Güell, Matthew J. Farrer, Li Chen, Valina L. Dawson, Ted M. Dawson, Zbigniew K. Wszolek, Owen A. Ross, Wolfdieter Springer in Brain. Published online November 2 2016 doi:10.1093/brain/aww261

Cite This NeuroscienceNews.com Article
Mayo Clinic “Single Mutation in Recessive Gene Increases Risk of Earlier Onset Parkinson’s Disease.” NeuroscienceNews. NeuroscienceNews, 2 November 2016.
<http://neurosciencenews.com/parkinsons-onset-genetics-5419/>.
Mayo Clinic (2016, November 2). Single Mutation in Recessive Gene Increases Risk of Earlier Onset Parkinson’s Disease. NeuroscienceNew. Retrieved November 2, 2016 from http://neurosciencenews.com/parkinsons-onset-genetics-5419/
Mayo Clinic “Single Mutation in Recessive Gene Increases Risk of Earlier Onset Parkinson’s Disease.” http://neurosciencenews.com/parkinsons-onset-genetics-5419/ (accessed November 2, 2016).

Abstract

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

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.

“Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism” by Andreas Puschmann, Fabienne C. Fiesel, Thomas R. Caulfield, Roman Hudec, Maya Ando, Dominika Truban, Xu Hou, Kotaro Ogaki, Michael G. Heckman, Elle D. James, Maria Swanberg, Itzia Jimenez-Ferrer, Oskar Hansson, Grzegorz Opala, Joanna Siuda, Magdalena Boczarska-Jedynak, Andrzej Friedman, Dariusz Koziorowski, Jan O. Aasly, Timothy Lynch, George D. Mellick, Megha Mohan, Peter A. Silburn, Yanosh Sanotsky, Carles Vilariño-Güell, Matthew J. Farrer, Li Chen, Valina L. Dawson, Ted M. Dawson, Zbigniew K. Wszolek, Owen A. Ross, Wolfdieter Springer in Brain. Published online November 2 2016 doi:10.1093/brain/aww261

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