Institute for Genetics

Köln, Germany

Institute for Genetics

Köln, Germany
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News Article | April 21, 2017
Site: www.eurekalert.org

Early in evolution, sugar intake and the regulation of life span were linked with each other. The hormone insulin is crucial here. It reduces blood sugar levels by binding to its receptor on the cell surface. However, many processes for stress management and survival are shut down at the same time. When there is a good supply of food, they appear unnecessary to the organism, although this reduces life expectancy over the long term. The insulin receptor thus acts like a brake on life expectancy. Genetically altered laboratory animals in which the insulin receptor no longer functions actually live much longer than normal. But how is the insulin receptor normally kept in check in our cells and tissue? A recent study by scientists at the Universities of Cologne and Bonn answers this fundamental question. The team of researchers shows that the protein CHIP plays a crucial role here. It acts like a disposal helper, in that it supplies the insulin receptor to the cellular breakdown and recycling systems by affixing a "green dot" in the form of the molecule ubiquitin onto the receptor. The life expectancy brake is thus released and CHIP unfurls anti-aging activity. "CHIP fulfils this function in nematodes, as well as in fruit flies and in humans. This makes the protein so interesting for us," explains Prof. Thorsten Hoppe, one of the two lead authors of the study from the Cluster of Excellence CECAD at the University of Cologne. When CHIP is missing, it leads to premature aging The findings were initially very surprising, as CHIP had so far been associated with completely different breakdown processes. Specifically, CHIP also disposes of faulty and damaged proteins, which increasingly occur at an older age and the accumulation of which leads to dementia and muscle weakness. The researchers actually recreated such degenerative illnesses in the nematode and in human cells and observed that there was no longer enough CHIP available to break down the insulin receptor. Premature aging is the result. Can the dream of a fountain of youth be made a reality and life extended in that researchers encourage cells to form more CHIP? "Unfortunately, it's not that easy," says lead author Prof. Jörg Höhfeld from the Institute for Cell Biology at the University of Bonn. When there is too much CHIP, undamaged proteins are also recycled and the organism is weakened. However, the researchers are already looking for mechanisms that control CHIP when breaking down the insulin receptor and that could one day also be used for new treatments. Publication: The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover, "Cell", DOI: 10.1016/j.cell.2017.04.003 Prof. Thorsten Hoppe CECAD Cologne and Institute for Genetics University of Cologne Tel. +49 221/47884218 E-mail: thorsten.hoppe@uni-koeln.de


Lauterbach M.A.R.,University of Bonn | Wunderlich F.T.,Institute for Genetics
Pflugers Archiv European Journal of Physiology | Year: 2017

The steadily increasing obesity epidemic affects currently 30% of western populations and is causative for numerous disorders. It has been demonstrated that immune cells such as macrophages reside in or infiltrate metabolic organs under obese conditions and cause the so-called low-grade inflammation or metaflammation that impairs insulin action thus leading to the development of insulin resistance. Here, we report on data that specifically address macrophage biology/physiology in obesity-induced inflammation and insulin resistance. © 2017, The Author(s).


Behrens A.,Cancer Research UK Research Institute | Behrens A.,King's College London | Van Deursen J.M.,Rochester College | Rudolph K.L.,Leibniz Institute for Age Research | And 3 more authors.
Nature Cell Biology | Year: 2014

Impairment of stem cell function contributes to the progressive deterioration of tissue maintenance and repair with ageing. Evidence is mounting that age-dependent accumulation of DNA damage in both stem cells and cells that comprise the stem cell microenvironment are partly responsible for stem cell dysfunction with ageing. Here, we review the impact of the various types of DNA damage that accumulate with ageing on stem cell functionality, as well as the development of cancer. We discuss DNA-damage-induced cell intrinsic and extrinsic alterations that influence these processes, and review recent advances in understanding systemic adjustments to DNA damage and how they affect stem cells. © 2014 Macmillan Publishers Limited. All rights reserved.


News Article | October 26, 2016
Site: www.nature.com

Hungary premier splits science academy Five foreign members of the Hungarian Academy of Sciences (HAS) have resigned in protest at what they consider to be antidemocratic actions by the populist government of Prime Minister Viktor Orbán (pictured) — and the academy’s failure to confront them. The protest was prompted by the closure this month of the country’s largest quality newspaper, Népszabadság, which had been critical of the government. On 19 October, the five, including Nobel-prizewinning neuroscientist Torsten Wiesel, published an open letter inviting other external members to resign and calling on the academy to “raise its voice in defence of freedom and justice in Hungary”. More than 150 academicians and HAS scientists published an open letter to academy president László Lovász on 14 October asking him to launch scholarly debates on the issues. He responded that the academy is not a political organization. JUNO trouble A computer glitch interrupted communication with NASA’s Juno spacecraft on 18 October. The probe entered into ‘safe mode’ about 13 hours before the closest approach to Jupiter in its second fly-by, but remained safely in its 53.4-day orbit around the giant planet. Juno, which has slipped into its temporary shut-down mode several times since its launch in 2011, aims to shed light on Jupiter’s origin, atmosphere and core. As Nature went to press, engineers were still trying to restore communications. Mars lander site A NASA spacecraft may have spotted the remains of Schiaparelli, the European Space Agency’s (ESA’s) missing Mars lander. Two new features on the red planet’s surface in images taken by the Mars Reconnaissance Orbiter are probably signs of Schiaparelli, ESA announced on 21 October. The lander was part of a joint European–Russian mission that reached Mars on 19 October. The first portion, the Trace Gas Orbiter, successfully entered orbit around the planet, while the lander began its descent to the surface. But towards the end of its six-minute landing procedure, Schiaparelli’s signal cut out and the craft has not been heard from since. A successful landing on Mars would have been a first for the agency. NSF pay rule The US National Science Foundation announced on 21 October that universities must now pay 10% of the salaries of faculty members who work with the agency to manage research programmes. The agency employs nearly 200 university researchers per year on a temporary basis, with the goal of learning from working scientists in different fields. Under a limited budget, the agency is aiming to reduce costs with the policy change, which also includes ending reimbursements for faculty members who miss out on consulting opportunities while working for the federal government. Kuwait DNA law Kuwait will scale back a controversial law that would have mandated the compulsory collection of DNA information from residents and visitors. The government had said that the data could be used to fight terrorism, but the law, passed in July 2015, faced widespread backlash from scientists and human-rights groups, as well as a legal challenge from a Kuwaiti law firm in September on constitutional grounds. On 19 October, Kuwait’s emir requested a review of the law. According to Kuwaiti lawyer Adel Abdulhadi, whose firm brought the challenge, the law will not be implemented in its current form and is likely to be amended so that it applies only to accused or convicted criminals. Glaciologist dies A US glaciologist died on a research trip in Antarctica on 22 October when the snowmobile he was riding fell into a crevasse. Gordon Hamilton (pictured) of the University of Maine in Orono had been working in a heavily crevassed area near the main US base, McMurdo Station, where the Ross and McMurdo ice shelves meet. Hamilton, who was 50, studied the stability of ice sheets and their larger role in the climate system, including sea-level rise. UN urban agenda Delegates from 167 countries agreed on 20 October to promote sustainable urban development at the United Nations’ Habitat III conference in Quito, Ecuador. Attendees adopted the New Urban Agenda, a non-binding document that sets broad goals to promote cleaner, healthier and more socially inclusive cities. It includes a call for universal access to modern energy services and a commitment to reduce greenhouse-gas emissions. However, scientific organizations such as Future Earth and the International Council for Science argue that the agreement lacks urgency, and call for an agenda that brings scientists on board and aligns with the UN Sustainable Development Goals. Europe’s trial data The European Medicines Agency (EMA), based in London, has started publishing details of the full clinical-trial data that it receives from drug companies. On 20 October, the agency published around 100 clinical reports (roughly 260,000 pages) about two EMA-approved medicines (carfilzomib, a cancer drug, and lesinurad, a gout treatment). The disclosures make the EMA the first major drug regulatory agency to publish the full results of clinical investigations that drug developers submit when they apply for the agency’s approval to market medicines. Species threat A court of appeal in the United States ruled on 24 October that federal agencies can rely on projections of future climate change to determine whether a species is threatened under the Endangered Species Act. The state of Alaska, several oil associations and groups representing Alaska’s indigenous people had claimed that a subspecies of the Pacific bearded seal (Erignathus barbatus nauticus) should not be protected by the act, because the animals were not yet in danger and climate predictions were conjecture. But the court rejected this, citing a climate projection that calculated that sea-ice loss would leave the species endangered by 2095. Nike funds science Phil Knight, co-founder of sports-clothing giant Nike, and his wife Penny announced on 17 October that they will give US$500 million to the University of Oregon in Eugene to create a Campus for Accelerating Scientific Impact. The centre will host dozens of scientists and hundreds of students and postdocs. The Knights’ philanthropic support is the first part of what the university hopes will be a $1-billion initiative focused on turning scientific discoveries into innovations. The gift is the among largest ever to a public US university. Phil Knight graduated from Oregon in 1959. Gene-drive centre An Indian philanthropic organization has awarded US$70 million to a California university to develop genetic tools for mosquito control. The gift from Tata Trusts in Mumbai, announced on 23 October, will fund the creation of the Tata Institute for Genetics and Society at the University of California, San Diego. The institute plans to develop gene-drive technologies — which can rapidly propagate a mutation through a population — to control malaria-carrying mosquitoes and improve crops, among other applications. Statistics prize Five statistical associations have created a prize in the hope of capturing broader recognition for their field. The inaugural US$75,000 International Prize in Statistics, announced on 19 October, was awarded to statistician David Cox at the University of Oxford, UK, for the ‘proportional hazards model’, which is widely used to identify risk factors and evaluate treatments across medical research. “Most people don’t have the slightest idea what statisticians do or why it matters,” says Ron Wasserstein, head of the American Statistical Association in Alexandria, Virginia. He hopes that the prize will encourage scientists to forge deeper collaborations with statisticians. The average atmospheric level of carbon dioxide reached the symbolic threshold of 400 parts per million (p.p.m.) in 2015, noted an annual report on 24 October. CO levels have crossed the threshold in certain months, but a global annual average has never done so in recorded history. The increase from 2014 was spurred by a strong El Niño event, which reduced CO uptake by natural vegetation because of drought. Preliminary data suggest that global CO may permanently top 400 p.p.m. in 2016. 7–18 November Delegates gather in Marrakesh, Morocco, for the United Nations COP22 climate summit and the first meeting of the parties to the Paris climate agreement. go.nature.com/2dtfo9v 12–16 November The 46th annual meeting of the Society for Neuroscience takes place in San Diego, California. go.nature.com/2el6nup


Fres J.M.,Institute for Genetics | Muller S.,Center for Molecular Medicine Cologne | Praefcke G.J.K.,Institute for Genetics
Journal of Lipid Research | Year: 2010

Over a hundred proteins in eukaryotic cells carry a C-terminal CaaX box sequence, which targets them for posttranslational isoprenylation of the cysteine residue. This modification, catalyzed by either farnesyl or geranylgeranyl transferase, converts them into peripheral membrane proteins. Isoprenylation is usually followed by proteolytic cleavage of the aaX tripeptide and methylation of the carboxyl group of the newly exposed isoprenylcysteine. The C-terminal modification regulates the cellular localization and biological activity of isoprenylated proteins. We have established a strategy to produce and purify recombinant farnesylated guanylate-binding protein 1 (hGBP1), a dynamin-related large GTPase. Our system is based on the coexpression of hGBP1 with the two subunits of human farnesyltransferase in Escherichia coli and a chromatographic separation of farnesylated and unmodified protein.jlr Farnesylated hGBP1 displays altered GTPase activity and is able to interact with liposomes in the activated state. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.


Sanchez-Lasheras C.,Institute for Genetics | Sanchez-Lasheras C.,University of Cologne | Sanchez-Lasheras C.,Max Planck Institute for Biology of Ageing | Christine Konner A.,Institute for Genetics | And 5 more authors.
Frontiers in Neuroendocrinology | Year: 2010

Body weight is tightly controlled in a species-specific range from insects to vertebrates and organisms have developed a complex regulatory network in order to avoid either excessive weight gain or chronic weight loss. Energy homeostasis, a term comprising all processes that aim to maintain stability of the metabolic state, requires a constant communication of the different organs involved; i.e. adipose tissue, skeletal muscle, liver, pancreas and the central nervous system (CNS). A tight hormonal network ensures rapid communication to control initiation and cessation of eating, nutrient processing and partitioning of the available energy within different organs and metabolic pathways. Moreover, recent experiments indicate that many of these homeostatic signals modulate the neural circuitry of food reward and motivation. Disturbances in each individual system can affect the maintenance and regulation of the others, making the analysis of energy homeostasis and its dysregulation highly complex. Though this cross-talk has been intensively studied for many years now, we are far from a complete understanding of how energy balance is maintained and multiple key questions remain unanswered. This review summarizes some of the latest developments in the field and focuses on the effects of leptin, insulin, and nutrient-related signals in the central regulation of feeding behavior. The integrated view, how these signals interact and the definition of functional neurocircuits in control of energy homeostasis, will ultimately help to develop new therapeutic interventions within the current obesity epidemic. © 2009 Elsevier Inc. All rights reserved.


News Article | November 8, 2016
Site: www.eurekalert.org

Cell death is an essential physiological process for all multicellular organisms. Throughout life, cells in many tissues die naturally and are replaced by new cells. A proper balance between the death and production of new cells is important for the maintenance of healthy tissue function and for regeneration after injury. Increased cell production coupled with reduced cell death can lead to tumor development. On the other hand, excessive cell death can cause tissue damage and disease. Normally our tissues are healthy, but some individuals develop inflammation and disease. "What causes inflammation?" asks Manolis Pasparakis, Professor at the Institute for Genetics of the University of Cologne, who is the senior author of the paper published on November 7th in Nature. "Can necroptosis be the trigger of inflammation in some cases and how is necroptosis regulated?" RIPK1 is a protein mainly known as an inducer of necroptosis. Researchers in the group of Manolis Pasparakis generated mice in which the RIPK1 gene was inactivated specifically in skin cells called keratinocytes. "We expected that the lack of RIPK1 would prevent necroptosis - but we observed the opposite. Keratinocytes in these mice died by necroptosis, causing skin inflammation. This was puzzling: How could the removal of RIPK1 cause necroptosis?" asked Snehlata Kumari, one of the three main authors of the paper. The researchers have now found an answer to this question: they discovered that RIPK1 inhibits another inducer of necroptosis, a protein called ZBP1. Genetic elimination of ZBP1 inhibited necroptosis and inflammation caused by RIPK1 deficiency. "ZBP1 was known as a sensor of DNA that contributes to immunity against some viruses, but so far it has not been implicated in inflammation," commented Chun Kim, who is also a main author of the study. The researchers asked how RIPK1 can inhibit ZBP1. To answer this question, they used CRISPR gene editing to modify three amino acids in the so called RHIM domain that allows RIPK1 to interact with other proteins regulating necroptosis. Mice expressing this mutant RIPK1 in all cells did not survive after birth. Moreover, the expression of mutated RIPK1 only in keratinocytes caused skin inflammation. Using a combination of genetic and biochemical experiments, the researchers could show that when the RHIM domain of RIPK1 was mutated, ZBP1 triggered necroptosis. This is what caused perinatal death, but also skin inflammation in adult mice. "This was a surprising result. These three amino acids of RIPK1 prevent ZBP1 from inducing necroptosis, and this is essential for mouse survival and the prevention of skin inflammation," said Juan Lin, one of the leading authors of the manuscript. "We made progress, but many pieces of the greater puzzle remain unclear," says Manolis Pasparakis. "ZBP1 has been known as a viral sensor, and now our results linked it to inflammation and disease. The triggers of chronic inflammation in humans are, in most cases, entirely unclear. Why does inflammation occur in a certain person at a certain moment? Bacterial and viral infections are discussed as possible triggers of chronic inflammation. In our work, we discovered the role of ZBP1 by experimentally altering RIPK1. Now we are wondering whether viruses or bacteria could activate ZBP1 to cause inflammation." The researchers are now working to put the next pieces of the puzzle in place and explore a possible link between ZBP1 and chronic inflammatory diseases in humans. Prof. Dr. Manolis Pasparakis Institute for Genetics and Cluster of Excellence CECAD Tel. +49 221 478 84351 pasparakis@uni-koeln.de


Hess M.E.,Max Planck Institute for Neurological Research | Hess M.E.,Institute for Genetics | Hess M.E.,University of Cologne | Bruning J.C.,Max Planck Institute for Neurological Research | And 2 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2014

Genome wide association studies undoubtedly linked variants of the fat mass and obesity-associated protein ( FTO) to obesity. To date, however, knowledge on the mechanisms coupling variants in the intron of the FTO gene to its expression or enzymatic activity to alter metabolism remains scarce. Until recently, the investigation of the molecular function of FTO had not led to conclusive results concerning the 'where', 'when' and 'how' of FTO activity. Finally, since FTO was identified as a RNA modifying enzyme, demethylating N6-methyladenosine on single stranded RNA, novel understanding of the molecular function is gathered. These and other studies suggest the requirement for a further reaching approach to further investigate FTO function, since the phenotype of aberrant FTO function may encompass more than just obesity. Taking these new insights and translating them into appropriate paradigms for functional research in humans may lead to a deeper understanding of the human physiology and disease. This article is part of a Special Issue entitled: From Genome to Function. © 2014 Elsevier B.V.


News Article | November 8, 2016
Site: www.sciencedaily.com

Cell death is an essential physiological process for all multicellular organisms. Throughout life, cells in many tissues die naturally and are replaced by new cells. A proper balance between the death and production of new cells is important for the maintenance of healthy tissue function and for regeneration after injury. Increased cell production coupled with reduced cell death can lead to tumor development. On the other hand, excessive cell death can cause tissue damage and disease. Normally our tissues are healthy, but some individuals develop inflammation and disease. "What causes inflammation?" asks Manolis Pasparakis, Professor at the Institute for Genetics of the University of Cologne, who is the senior author of the paper published on November 7th in Nature. "Can necroptosis be the trigger of inflammation in some cases and how is necroptosis regulated?" RIPK1 is a protein mainly known as an inducer of necroptosis. Researchers in the group of Manolis Pasparakis generated mice in which the RIPK1 gene was inactivated specifically in skin cells called keratinocytes. "We expected that the lack of RIPK1 would prevent necroptosis -- but we observed the opposite. Keratinocytes in these mice died by necroptosis, causing skin inflammation. This was puzzling: How could the removal of RIPK1 cause necroptosis?" asked Snehlata Kumari, one of the three main authors of the paper. The researchers have now found an answer to this question: they discovered that RIPK1 inhibits another inducer of necroptosis, a protein called ZBP1. Genetic elimination of ZBP1 inhibited necroptosis and inflammation caused by RIPK1 deficiency. "ZBP1 was known as a sensor of DNA that contributes to immunity against some viruses, but so far it has not been implicated in inflammation," commented Chun Kim, who is also a main author of the study. The researchers asked how RIPK1 can inhibit ZBP1. To answer this question, they used CRISPR gene editing to modify three amino acids in the so called RHIM domain that allows RIPK1 to interact with other proteins regulating necroptosis. Mice expressing this mutant RIPK1 in all cells did not survive after birth. Moreover, the expression of mutated RIPK1 only in keratinocytes caused skin inflammation. Using a combination of genetic and biochemical experiments, the researchers could show that when the RHIM domain of RIPK1 was mutated, ZBP1 triggered necroptosis. This is what caused perinatal death, but also skin inflammation in adult mice. "This was a surprising result. These three amino acids of RIPK1 prevent ZBP1 from inducing necroptosis, and this is essential for mouse survival and the prevention of skin inflammation," said Juan Lin, one of the leading authors of the manuscript. "We made progress, but many pieces of the greater puzzle remain unclear," says Manolis Pasparakis. "ZBP1 has been known as a viral sensor, and now our results linked it to inflammation and disease. The triggers of chronic inflammation in humans are, in most cases, entirely unclear. Why does inflammation occur in a certain person at a certain moment? Bacterial and viral infections are discussed as possible triggers of chronic inflammation. In our work, we discovered the role of ZBP1 by experimentally altering RIPK1. Now we are wondering whether viruses or bacteria could activate ZBP1 to cause inflammation." The researchers are now working to put the next pieces of the puzzle in place and explore a possible link between ZBP1 and chronic inflammatory diseases in humans.


News Article | November 10, 2016
Site: www.medicalnewstoday.com

Cell death is an essential physiological process for all multicellular organisms. Throughout life, cells in many tissues die naturally and are replaced by new cells. A proper balance between the death and production of new cells is important for the maintenance of healthy tissue function and for regeneration after injury. Increased cell production coupled with reduced cell death can lead to tumor development. On the other hand, excessive cell death can cause tissue damage and disease. Normally our tissues are healthy, but some individuals develop inflammation and disease. "What causes inflammation?" asks Manolis Pasparakis, Professor at the Institute for Genetics of the University of Cologne, who is the senior author of the paper published Nature. "Can necroptosis be the trigger of inflammation in some cases and how is necroptosis regulated?" RIPK1 is a protein mainly known as an inducer of necroptosis. Researchers in the group of Manolis Pasparakis generated mice in which the RIPK1 gene was inactivated specifically in skin cells called keratinocytes. "We expected that the lack of RIPK1 would prevent necroptosis - but we observed the opposite. Keratinocytes in these mice died by necroptosis, causing skin inflammation. This was puzzling: How could the removal of RIPK1 cause necroptosis?" asked Snehlata Kumari, one of the three main authors of the paper. The researchers have now found an answer to this question: they discovered that RIPK1 inhibits another inducer of necroptosis, a protein called ZBP1. Genetic elimination of ZBP1 inhibited necroptosis and inflammation caused by RIPK1 deficiency. "ZBP1 was known as a sensor of DNA that contributes to immunity against some viruses, but so far it has not been implicated in inflammation," commented Chun Kim, who is also a main author of the study. The researchers asked how RIPK1 can inhibit ZBP1. To answer this question, they used CRISPR gene editing to modify three amino acids in the so called RHIM domain that allows RIPK1 to interact with other proteins regulating necroptosis. Mice expressing this mutant RIPK1 in all cells did not survive after birth. Moreover, the expression of mutated RIPK1 only in keratinocytes caused skin inflammation. Using a combination of genetic and biochemical experiments, the researchers could show that when the RHIM domain of RIPK1 was mutated, ZBP1 triggered necroptosis. This is what caused perinatal death, but also skin inflammation in adult mice. "This was a surprising result. These three amino acids of RIPK1 prevent ZBP1 from inducing necroptosis, and this is essential for mouse survival and the prevention of skin inflammation," said Juan Lin, one of the leading authors of the manuscript. "We made progress, but many pieces of the greater puzzle remain unclear," says Manolis Pasparakis. "ZBP1 has been known as a viral sensor, and now our results linked it to inflammation and disease. The triggers of chronic inflammation in humans are, in most cases, entirely unclear. Why does inflammation occur in a certain person at a certain moment? Bacterial and viral infections are discussed as possible triggers of chronic inflammation. In our work, we discovered the role of ZBP1 by experimentally altering RIPK1. Now we are wondering whether viruses or bacteria could activate ZBP1 to cause inflammation." The researchers are now working to put the next pieces of the puzzle in place and explore a possible link between ZBP1 and chronic inflammatory diseases in humans.

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