Institute of Developmental Genetics

München, Germany

Institute of Developmental Genetics

München, Germany
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News Article | November 15, 2016
Site: www.eurekalert.org

Ferroptosis is a recently discovered form of cell death, which is still only partially understood. Scientists at the Helmholtz Zentrum München have now identified an enzyme that plays a key role in generating the signal that initiates cell death. Their findings, published in two articles in the journal Nature Chemical Biology, could now give new impetus to research into the fields of cancer, neurodegeneration and other degenerative diseases. The term ferroptosis was first coined in 2012. It is derived from the Greek word ptosis, meaning "a fall", and ferrum, the Latin word for iron, and describes a form of regulated necrotic cell death in which iron appears to play an important role. "The individual mechanisms involved in this type of cell death remain only partly understood, and our findings make an important contribution towards a better understanding of ferroptotic cell death," says study leader Dr. Marcus Conrad, who is heading a research group at the Institute of Developmental Genetics at the Helmholtz Zentrum München. Along with his team and colleagues from the University of Pittsburgh, he was able to show that ACSL4*, an enzyme involved in the metabolism of fatty acids, plays a central role in ferroptosis. In order for the lethal mechanism to be triggered, a certain amount of specific oxidized lipid molecules must be present in membranes. "Acsl4 is critically involved in shaping the cellular lipid composition by storing more poly-unsaturated long-chain fatty acids in cellular membranes, thereby providing the starting materials for the generation of the lethal lipid signals driving ferroptosis" explains PhD student Sebastian Doll, first author of one of the two studies. "Previously it was assumed that iron-dependent lipid oxidation occurs randomly; however, our data now demonstrate that ACSL4 centrally contributes to the formation of oxidized lipid death signals in ferroptosis." Potential applications for the treatment of cancer and neurodegenerative diseases Although the term 'cell death' is generally viewed as an adverse event and thus has a rather negative image, it has been shown - particularly in the context of cancer - that the selective destruction of aberrant cells is vital for the human body. The scientists therefore examined the role of ACSL4 in this context. They showed that a subset of breast cancer cells (i.e. triple negative breast cancer cells) that do not produce ACSL4 are extremely resistant to ferroptosis, while those that express the enzyme respond very sensitively to ferroptosis induction. "This is a highly interesting finding given the fact that the presence of ACSL4 determines whether or not cells can embark on the ferroptosis pathway" explains Dr. José Pedro Friedmann Angeli, who was centrally involved in both studies. It is thus well conceivable, he says, that the molecule could be used as a biomarker in cancer patient stratification. The researchers also provided the first molecular approach for targeting ACSL4 in the signalling pathway. In a model experiment using thiazolidinediones, a class of active compounds commonly used in the treatment of diabetes, they succeeded in slowing down the process of ferroptosis. "Our intriguing insights that the ACSL4 enzyme plays a substantial role in the process of cell death provide novel cues for yet-unrecognized therapeutic approaches towards inhibiting ferroptosis in degenerative diseases or inducing ferroptosis in certain tumor diseases," says study leader Dr. Conrad. In particular, tumors that are otherwise very difficult to treat with standard chemotherapy might be amenable for ferroptosis therapy, the researchers say. * Acyl-CoA is a group of coenzymes involved in the metabolism of fatty acids. ACSL4 stands for Acyl-CoA synthetase long-chain family member 4. Background: Up until now ferroptosis is only partially understood. However, the importance of cellular suicide has already been impressively documented by research concerning apoptosis, the first identified cell death pathway, which has been explored by far more comprehensively throughout the last decades than ferroptosis. Moreover, ferroptosis appears to play a key role in cancer and in cell demise in response to oxidative stress (e.g. in neurons). Previously, only a few essential molecules, such as glutathione peroxidase 4 (GPX4), have been implicated in the ferroptotic process. Kagan, VE. et al. (2016): Oxidized Arachidonic and Adrenic PEs Navigate Cells to Ferroptosis. Nature Chemical Biology, doi: 10.1038/nchembio.2238 http://www. The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www. Rising life expectancy is causing an increase in age-related, but also sociological and environmental, influences on the genes. The Institute of Developmental Genetics (IDG) examines these changes in genetic material. In the Mouse Genetics group, genetic animal models are developed to investigate various diseases. These models are analyzed in the Disease Modelling research group in order to identify gene functions and cell processes and evaluate the influence of the environment and aging processes. The group focuses on the examination of neurological and psychiatric diseases. http://www. The Institute of Human Genetics (IHG) at the Helmholtz Zentrum München and the Technical University of Munich: The Institute is concerned with identifying genes associated with disease and characterizing their functions. The main aim of the research projects is to develop disease-related genetic variation in humans and mice as well as to develop chromosome analysis techniques and new methods for dealing with specific issues in the sphere of pre- and post-natal diagnostics and tumor cytogenetics. http://www. The research objective of the Institute of Experimental Genetics (IEG) is to elucidate the causes and pathogenesis of human diseases. Due to its prominent role in interdisciplinary and international consortia, the IEG is a global leader in the systemic study of mouse models for human diseases and the elucidation of involved genes. The main focus is on metabolic diseases such as diabetes. The IEG is part of the Helmholtz Diabetes Center (HDC). http://www. The Institute of Pathology (PATH) contributes to the identification and characterization of molecular mechanisms and pathways, which are relevant for disease development and progression. We endeavor to understand the interplay between environment and genetic, and to identify novel targets for therapeutic intervention. http://www. Contact for the media: Department of Communication, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel. +49 89 3187 2238 - Fax: +49 89 3187 3324 - E-mail: presse@helmholtz-muenchen.de Scientific Contact at Helmholtz Zentrum München: Dr. Marcus Conrad, Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel. +49 89 3187 4608, E-mail: marcus.conrad@helmholtz-muenchen.de


Ehm O.,Institute of Developmental Genetics | Goritz C.,Karolinska Institutet | Covic M.,Institute of Developmental Genetics | Schaffner I.,Institute of Developmental Genetics | And 11 more authors.
Journal of Neuroscience | Year: 2010

The generation of new neurons from neural stem cells in the adult hippocampal dentate gyrus contributes to learning and mood regulation. To sustain hippocampal neurogenesis throughout life, maintenance of the neural stem cell pool has to be tightly controlled. We found that the Notch/RBPJκ- signaling pathway is highly active in neural stem cells of the adult mouse hippocampus. Conditional inactivation of RBPJκ in neural stem cells in vivo resulted in increased neuronal differentiation of neural stem cells in the adult hippocampus at an early time point and depletion of the Sox2-positive neural stem cell pool and suppression of hippocampal neurogenesis at a later time point. Moreover, RBPJκ-deficient neural stem cells displayed impaired self-renewal in vitro and loss of expression of the transcription factor Sox2. Interestingly, we found that Notch signaling increases Sox2 promoter activity and Sox2 expression in adult neural stem cells. In addition, activated Notch and RBPJκ were highly enriched on the Sox2 promoter in adult hippocampal neural stem cells, thus identifying Sox2 as a direct target of Notch/RBPJκ signaling. Finally, we found that overexpression of Sox2 can rescue the self-renewal defect in RBPJκ-deficient neural stem cells. These results identify RBPJκ-dependent pathways as essential regulators of adult neural stem cell maintenance and suggest that the actions of RBPJκ are, at least in part, mediated by control of Sox2 expression. Copyright © 2010 the authors.


Schulz S.,TU Munich | Schulz S.,Research Unit for Environmental Genomics | Giebler J.,Helmholtz Center for Environmental Research | Chatzinotas A.,Helmholtz Center for Environmental Research | And 5 more authors.
ISME Journal | Year: 2012

Alkanes are major constituents of plant-derived waxy materials. In this study, we investigated the abundance, community structure and activity of bacteria harbouring the alkane monooxygenase gene alkB, which catalyses a major step in the pathway of aerobic alkane degradation in the litter layer, the litter-soil interface and in bulk soil at three time points during the degradation of maize and pea plant litter (2, 8 and 30 weeks) to improve our understanding about drivers for microbial performance in different soil compartments. Soil cores of different soil textures (sandy and silty) were taken from an agricultural field and incubated at constant laboratory conditions. The abundance of alkB genes and transcripts (by qPCR) as well as the community structure (by terminal restriction fragment polymorphism fingerprinting) were measured in combination with the concentrations and composition of alkanes. The results obtained indicate a clear response pattern of all investigated biotic and abiotic parameters depending on the applied litter material, the type of soil used, the time point of sampling and the soil compartment studied. As expected the distribution of alkanes of different chain length formed a steep gradient from the litter layer to the bulk soil. Mainly in the two upper soil compartments community structure and abundance patterns of alkB were driven by the applied litter type and its degradation. Surprisingly, the differences between the compartments in one soil were more pronounced than the differences between similar compartments in the two soils studied. This indicates the necessity for analysing processes in different soil compartments to improve our mechanistic understanding of the dynamics of distinct functional groups of microbes. © 2012 International Society for Microbial Ecology All rights reserved.


News Article | November 15, 2016
Site: www.sciencedaily.com

Ferroptosis is a recently discovered form of cell death, which is still only partially understood. Scientists at the Helmholtz Zentrum München have now identified an enzyme that plays a key role in generating the signal that initiates cell death. Their findings, published in two articles in the journal Nature Chemical Biology, could now give new impetus to research into the fields of cancer, neurodegeneration and other degenerative diseases. The term ferroptosis was first coined in 2012. It is derived from the Greek word ptosis, meaning "a fall," and ferrum, the Latin word for iron, and describes a form of regulated necrotic cell death in which iron appears to play an important role. "The individual mechanisms involved in this type of cell death remain only partly understood, and our findings make an important contribution towards a better understanding of ferroptotic cell death," says study leader Dr. Marcus Conrad, who is heading a research group at the Institute of Developmental Genetics at the Helmholtz Zentrum München. Along with his team and colleagues from the University of Pittsburgh, he was able to show that ACSL4, an enzyme involved in the metabolism of fatty acids, plays a central role in ferroptosis. In order for the lethal mechanism to be triggered, a certain amount of specific oxidized lipid molecules must be present in membranes. "Acsl4 is critically involved in shaping the cellular lipid composition by storing more poly-unsaturated long-chain fatty acids in cellular membranes, thereby providing the starting materials for the generation of the lethal lipid signals driving ferroptosis" explains PhD student Sebastian Doll, first author of one of the two studies. "Previously it was assumed that iron-dependent lipid oxidation occurs randomly; however, our data now demonstrate that ACSL4 centrally contributes to the formation of oxidized lipid death signals in ferroptosis." Potential applications for the treatment of cancer and neurodegenerative diseases Although the term 'cell death' is generally viewed as an adverse event and thus has a rather negative image, it has been shown -- particularly in the context of cancer -- that the selective destruction of aberrant cells is vital for the human body. The scientists therefore examined the role of ACSL4 in this context. They showed that a subset of breast cancer cells (i.e. triple negative breast cancer cells) that do not produce ACSL4 are extremely resistant to ferroptosis, while those that express the enzyme respond very sensitively to ferroptosis induction. "This is a highly interesting finding given the fact that the presence of ACSL4 determines whether or not cells can embark on the ferroptosis pathway" explains Dr. José Pedro Friedmann Angeli, who was centrally involved in both studies. It is thus well conceivable, he says, that the molecule could be used as a biomarker in cancer patient stratification. The researchers also provided the first molecular approach for targeting ACSL4 in the signalling pathway. In a model experiment using thiazolidinediones, a class of active compounds commonly used in the treatment of diabetes, they succeeded in slowing down the process of ferroptosis. "Our intriguing insights that the ACSL4 enzyme plays a substantial role in the process of cell death provide novel cues for yet-unrecognized therapeutic approaches towards inhibiting ferroptosis in degenerative diseases or inducing ferroptosis in certain tumor diseases," says study leader Dr. Conrad. In particular, tumors that are otherwise very difficult to treat with standard chemotherapy might be amenable for ferroptosis therapy, the researchers say.


News Article | November 15, 2016
Site: phys.org

Ferroptosis is a recently discovered form of cell death, which is still only partially understood. Scientists at the Helmholtz Zentrum München have now identified an enzyme that plays a key role in generating the signal that initiates cell death. Their findings, published in two articles in the journal Nature Chemical Biology, could now give new impetus to research into the fields of cancer, neurodegeneration and other degenerative diseases. The term ferroptosis was first coined in 2012. It is derived from the Greek word ptosis, meaning "a fall", and ferrum, the Latin word for iron, and describes a form of regulated necrotic cell death in which iron appears to play an important role. "The individual mechanisms involved in this type of cell death remain only partly understood, and our findings make an important contribution towards a better understanding of ferroptotic cell death," says study leader Dr. Marcus Conrad, who is heading a research group at the Institute of Developmental Genetics at the Helmholtz Zentrum München. Along with his team and colleagues from the University of Pittsburgh, he was able to show that ACSL4, an enzyme involved in the metabolism of fatty acids, plays a central role in ferroptosis. In order for the lethal mechanism to be triggered, a certain amount of specific oxidized lipid molecules must be present in membranes. "Acsl4 is critically involved in shaping the cellular lipid composition by storing more poly-unsaturated long-chain fatty acids in cellular membranes, thereby providing the starting materials for the generation of the lethal lipid signals driving ferroptosis" explains PhD student Sebastian Doll, first author of one of the two studies. "Previously it was assumed that iron-dependent lipid oxidation occurs randomly; however, our data now demonstrate that ACSL4 centrally contributes to the formation of oxidized lipid death signals in ferroptosis." Potential applications for the treatment of cancer and neurodegenerative diseases Although the term 'cell death' is generally viewed as an adverse event and thus has a rather negative image, it has been shown – particularly in the context of cancer – that the selective destruction of aberrant cells is vital for the human body. The scientists therefore examined the role of ACSL4 in this context. They showed that a subset of breast cancer cells (i.e. triple negative breast cancer cells) that do not produce ACSL4 are extremely resistant to ferroptosis, while those that express the enzyme respond very sensitively to ferroptosis induction. "This is a highly interesting finding given the fact that the presence of ACSL4 determines whether or not cells can embark on the ferroptosis pathway" explains Dr. José Pedro Friedmann Angeli, who was centrally involved in both studies. It is thus well conceivable, he says, that the molecule could be used as a biomarker in cancer patient stratification. The researchers also provided the first molecular approach for targeting ACSL4 in the signalling pathway. In a model experiment using thiazolidinediones, a class of active compounds commonly used in the treatment of diabetes, they succeeded in slowing down the process of ferroptosis. "Our intriguing insights that the ACSL4 enzyme plays a substantial role in the process of cell death provide novel cues for yet-unrecognized therapeutic approaches towards inhibiting ferroptosis in degenerative diseases or inducing ferroptosis in certain tumor diseases," says study leader Dr. Conrad. In particular, tumors that are otherwise very difficult to treat with standard chemotherapy might be amenable for ferroptosis therapy, the researchers say. More information: Sebastian Doll et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition, Nature Chemical Biology (2016). DOI: 10.1038/nchembio.2239 Valerian E Kagan et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis, Nature Chemical Biology (2016). DOI: 10.1038/nchembio.2238


von Wolff G.,Max Planck Institute of Psychiatry | Avrabos C.,Max Planck Institute of Psychiatry | Stepan J.,Max Planck Institute of Psychiatry | Wurst W.,Max Planck Institute of Psychiatry | And 6 more authors.
Journal of Psychiatric Research | Year: 2011

Corticotropin-releasing hormone (CRH) is thought to play an important role in the pathophysiology of stress-related psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). However, knowledge about the actions of CRH at the neuronal network level is only scarce. Here, we examined whether CRH affects neuronal activity propagation through the hippocampal formation (HF), a brain region which is likely to be involved in MDD and PTSD. For this purpose, we applied voltage-sensitive dye imaging (VSDI) to specifically cut hippocampal brain slices obtained from adult mice. This approach allowed us to investigate evoked neuronal activity propagation through the HF with micrometer spatial and millisecond temporal resolution. Application of CRH (50 nM) to slices increased neuronal activity propagation from the dentate gyrus (DG) to the CA1 subfield. This effect of CRH was caused by amplification of neuronal excitation on its passage through the HF and absent in mice lacking the CRH receptor type 1 (CRHR1). In conclusion, our study presents a VSDI assay for the investigation of neuronal activity propagation through the HF and demonstrates that CRH, via CRHR1, enhances this activity propagation. This effect of CRH might contribute to alterations of memory formation seen in MDD and PTSD. Moreover, it could influence hippocampal regulation of hypothalamic-pituitary-adrenal axis (HPA-axis) activity. © 2010 Elsevier Ltd.


Sengupta A.,U.S. National Institutes of Health | Sengupta A.,Georgetown University | Lichti U.F.,U.S. National Institutes of Health | Carlson B.A.,U.S. National Institutes of Health | And 9 more authors.
Journal of Investigative Dermatology | Year: 2013

Selenoproteins are essential molecules for the mammalian antioxidant network. We previously demonstrated that targeted loss of all selenoproteins in mouse epidermis disrupted skin and hair development, and caused premature death. In the current study, we targeted specific selenoproteins for epidermal deletion to determine whether similar phenotypes developed. Keratinocyte- specific knockout mice lacking either the glutathione peroxidase 4 (GPx4) or thioredoxin reductase 1 (TR1) gene were generated by cre-lox technology using K14-cre. TR1 knockout mice had a normal phenotype in resting skin, whereas GPx4 loss in the epidermis caused epidermal hyperplasia, dermal inflammatory infiltrate, dysmorphic hair follicles, and alopecia in perinatal mice. Unlike epidermal ablation of all selenoproteins, mice ablated for GPx4 recovered after 5 weeks and had a normal life span. GPx1 and TR1 were upregulated in the skin and keratinocytes of GPx4-knockout mice. GPx4 deletion reduces keratinocyte adhesion in culture and increases lipid peroxidation and cyclooxygenase-2 (COX-2) levels in cultured keratinocytes and whole skin. Feeding a COX-2 inhibitor to nursing mothers partially prevents development of the abnormal skin phenotype in knockout pups. These data link the activity of cutaneous GPx4 to the regulation of COX-2 and hair follicle morphogenesis, and provide insight into the function of individual selenoprotein activity in maintaining cutaneous homeostasis. © 2013 The Society for Investigative Dermatology.


Desbordes S.C.,Sloan Kettering Cancer Center | Desbordes S.C.,Institute of Developmental Genetics | Studer L.,Sloan Kettering Cancer Center
Nature Protocols | Year: 2013

The increasing use of human pluripotent stem cells (hPSCs) as a source of cells for drug discovery, cytotoxicity assessment and disease modeling requires their adaptation to large-scale culture conditions and screening formats. Here, we describe a simple and robust protocol for the adaptation of human embryonic stem cells (hESCs) to high-throughput screening (HTS). This protocol can also be adapted to human induced pluripotent stem cells (hiPSCs) and high-content screening (HCS). We also describe a 7-d assay to identify compounds with an effect on hESC self-renewal and differentiation. This assay can be adapted to a variety of applications. The procedure involves the culture expansion of hESCs, their adaptation to 384-well plates, the addition of small molecules or other factors, and finally data acquisition and processing. In this protocol, the optimal number of hESCs plated in 384-well plates has been adapted to HTS/HCS assays of 7 d. © 2012 Nature America, Inc. All rights reserved.

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