LIMES Institute

Bonn, Germany

LIMES Institute

Bonn, Germany

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News Article | May 19, 2017
Site: www.eurekalert.org

A study led by the University of Bonn opens a new perspective with regard to the development of dementia. The scientists blocked the breakdown of a certain fat molecule in the mouse brain. As a result the animals exhibited learning and memory problems. Also the quantity of Alzheimer-specific proteins in their brains increased significantly. The researchers now have a clue as to why the mice become dumb. The results are published in the renowned scientific journal "Autophagy". Apart from water, our brain is rich in lipids -- in plain language: fats. The lipids act, for instance, as an insulating layer around the nerve fibers and thus prevent short circuits. However, they are also a main component in the delicate membranes that surround the brain cells. Sphingolipids, a special lipid type are highly enriched in the brain. One of their degradation products, S1P, may play a central role in the development of Alzheimer's and other forms of dementia. "We raised mice that are no longer able to break down S1P in large parts of their brain," explains Dr. Gerhild van Echten-Deckert. "The animals then displayed severely reduced learning and memory performance." Van Echten-Deckert undertakes research at the LIMES Institute at the University of Bonn (the acronym stands for "Life and Medical Sciences") as an assistant professor. For a long time, she has been one of the few experts in the world interested in the role of S1P in the brain. The new study could fundamentally change this, as the researchers at the University of Bonn, Jena University Hospital, the German Center for Neurodegenerative Diseases (DZNE) and from San Francisco and Madrid were able to show what far-reaching consequences disrupted S1P breakdown has. Normally, S1P is broken down into simpler products. One such breakdown product generated is important for a vital metabolic pathway - called autophagy. The word autophagy (literally translates to "self-eating") and the pathway enables cells to digest and recycle their own components. The cells are thus cleared from defective proteins and cell organelles that no longer function properly. Intracellular waste disposal works in two steps: first, it packs the waste in tiny "garbage bags". These then merge with other "bags" that contain highly reactive enzymes. The enzymes "shred" the content of the garbage bags and thus dispose it off. The break-down product of S1P is involved in packing the waste into the intracellular garbage bags. "If S1P is not broken down, fewer closed garbage bags are formed; autophagy then no longer works accurately," explains the first author of the study Daniel Mitroi, who has recently completed his PhD at the LIMES Institute. "Harmful substances thus accumulated in the brains of our mice. These included the protein APP, which plays a key role in the development of Alzheimer's." As autophagy is crucial for normal functioning of the brain, improper intracellular waste disposal results in severe illnesses. Therefore last year the Nobel Prize in Medicine was awarded to the Japanese scientist Yoshinori Ohsumi for his notable work on this vital mechanism. The results of the current study shed light on a previously overlooked mechanism for dementia development. "In the long term, our work may contribute towards developing successful treatment strategies for brain disorders," hopes Dr. van Echten-Deckert.


News Article | May 19, 2017
Site: www.sciencedaily.com

A study led by the University of Bonn opens a new perspective with regard to the development of dementia. The scientists blocked the breakdown of a certain fat molecule in the mouse brain. As a result the animals exhibited learning and memory problems. Also the quantity of Alzheimer-specific proteins in their brains increased significantly. The researchers now have a clue as to why the mice become dumb. The results are published in the scientific journal Autophagy. Apart from water, our brain is rich in lipids -- in plain language: fats. The lipids act, for instance, as an insulating layer around the nerve fibers and thus prevent short circuits. However, they are also a main component in the delicate membranes that surround the brain cells. Sphingolipids, a special lipid type are highly enriched in the brain. One of their degradation products, S1P, may play a central role in the development of Alzheimer's and other forms of dementia. "We raised mice that are no longer able to break down S1P in large parts of their brain," explains Dr. Gerhild van Echten-Deckert. "The animals then displayed severely reduced learning and memory performance." Van Echten-Deckert undertakes research at the LIMES Institute at the University of Bonn (the acronym stands for "Life and Medical Sciences") as an assistant professor. For a long time, she has been one of the few experts in the world interested in the role of S1P in the brain. The new study could fundamentally change this, as the researchers at the University of Bonn, Jena University Hospital, the German Center for Neurodegenerative Diseases (DZNE) and from San Francisco and Madrid were able to show what far-reaching consequences disrupted S1P breakdown has. Normally, S1P is broken down into simpler products. One such breakdown product generated is important for a vital metabolic pathway -- called autophagy. The word autophagy (literally translates to "self-eating") and the pathway enables cells to digest and recycle their own components. The cells are thus cleared from defective proteins and cell organelles that no longer function properly. Intracellular waste disposal works in two steps: first, it packs the waste in tiny "garbage bags." These then merge with other "bags" that contain highly reactive enzymes. The enzymes "shred" the content of the garbage bags and thus dispose it off. The break-down product of S1P is involved in packing the waste into the intracellular garbage bags. "If S1P is not broken down, fewer closed garbage bags are formed; autophagy then no longer works accurately," explains the first author of the study Daniel Mitroi, who has recently completed his PhD at the LIMES Institute. "Harmful substances thus accumulated in the brains of our mice. These included the protein APP, which plays a key role in the development of Alzheimer's." As autophagy is crucial for normal functioning of the brain, improper intracellular waste disposal results in severe illnesses. Therefore last year the Nobel Prize in Medicine was awarded to the Japanese scientist Yoshinori Ohsumi for his notable work on this vital mechanism. The results of the current study shed light on a previously overlooked mechanism for dementia development. "In the long term, our work may contribute towards developing successful treatment strategies for brain disorders," hopes Dr. van Echten-Deckert.


Richter D.,University of Hohenheim | Richter D.,LIMES Institute | Katz B.,Hebrew University of Jerusalem | Oberacker T.,University of Hohenheim | And 4 more authors.
Journal of Biological Chemistry | Year: 2011

In Drosophila photoreceptors the transient receptor potential- like (TRPL), but not theTRPchannels undergo light-dependent translocation between the rhabdomere and cell body. Here we studied which of theTRPLchannel segments are essential for translocation and why the TRP channels are required for inducing TRPL translocation. We generated transgenic flies expressing chimeric TRP and TRPL proteins that formed functional light-activated channels. Translocation was induced only in chimera containing both the N- and C-terminal segments of TRPL. Using an inactive trp mutation and overexpressing the Na +/ Ca 2+ exchanger revealed that the essential function of the TRP channels in TRPL translocation is to enhance Ca 2+-influx. These results indicate that motifs present at both the N and C termini as well as sustained Ca 2+ entry are required for proper channel translocation. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.


Draffehn A.M.,Max Planck Institute for Plant Breeding Research | Draffehn A.M.,LIMES Institute | Durek P.,Max Planck Institute of Molecular Plant Physiology | Durek P.,Charité - Medical University of Berlin | And 5 more authors.
Plant, Cell and Environment | Year: 2012

Biochemical, molecular and genetic studies emphasize the role of the potato vacuolar invertase Pain-1 in the accumulation of reducing sugars in potato tubers upon cold storage, and thereby its influence on the quality of potato chips and French fries. Previous studies showed that natural Pain-1 cDNA alleles were associated with better chip quality and higher tuber starch content. In this study, we focused on the functional characterization of these alleles. A genotype-dependent transient increase of total Pain-1 transcript levels in cold-stored tubers of six different genotypes as well as allele-specific expression patterns were detected. 3D modelling revealed putative structural differences between allelic Pain-1 proteins at the molecule's surface and at the substrate binding site. Furthermore, the yeast SUC2 mutant was complemented with Pain-1 cDNA alleles and enzymatic parameters of the heterologous expressed proteins were measured at 30 and 4°C. Significant differences between the alleles were detected. The observed functional differences between Pain-1 alleles did not permit final conclusions on the mechanism of their association with tuber quality traits. Our results show that natural allelic variation at the functional level is present in potato, and that the heterozygous genetic background influences the manifestation of this variation. © 2012 Blackwell Publishing Ltd.


Valero J.,Institute of Chemical Research of Catalonia | Valero J.,LIMES Institute | Shiraishi T.,Copenhagen University | De Mendoza J.,Institute of Chemical Research of Catalonia | Nielsen P.E.,Copenhagen University
ChemBioChem | Year: 2015

A series of peptide nucleic acid-oligo(bicycloguanidinium) (PNA-BGn) conjugates were synthesized and characterized in terms of cellular antisense activity by using the pLuc750HeLa cell splice correction assay. PNA-BG4 conjugates exhibited low micromolar antisense activity, and their cellular activity required the presence of a hydrophobic silyl terminal protecting group on the oligo(BG) ligand and a minimum of four guanidinium units. Surprisingly, a nonlinear dose-response with an activity threshold around 3-4 μM, indicative of large cooperativity, was observed. Supported by light scattering and electron microscopy analyses, we propose that the activity, and thus cellular delivery, of these lipo-PNA-BG4 conjugates is dependent on self-assembled nanoaggregates. Finally, cellular activity was enhanced by the presence of serum. Therefore we conclude that the lipo-BG-PNA conjugates exhibit an unexpected mechanism for cell delivery and are of interest for further in vivo studies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Calderon R.M.K.,The Interdisciplinary Center | Valero J.,Institute of Chemical Research of Catalonia | Valero J.,LIMES Institute | Grimm B.,The Interdisciplinary Center | And 2 more authors.
Journal of the American Chemical Society | Year: 2014

Herein, we report the synthesis of guanidinium bis-porphyrin tweezers 1 and fullerene carboxylate 3, their assembly into a novel supramolecular 1@3 electron donor-acceptor hybrid, and its characterization. In solution, the binding constant affording 1@3 is exceptionally high. 1@3, which features a highly confined topography, builds up from a combination of guanidinium- carboxylate hydrogen bonding and π-π stacking/charge-transfer motifs. The latter is governed by interactions between the electron-donating porphyrin and the electron-accepting fullerene. Importantly, positive cooperativity between the applied binding motifs is corroborated by a number of experimental techniques, such as NMR, absorption, fluorescence, etc. In addition, transient absorption experiments shed light onto electron-transfer processes taking place in the ground state and upon photoexcitation. In fact, porphyrin excitation powers an electron transfer to the fullerene yielding charge separated state lifetimes in the nanosecond regime. © 2014 American Chemical Society.


Lohmann F.,LIMES Institute | Ackermann D.,LIMES Institute | Famulok M.,LIMES Institute
Journal of the American Chemical Society | Year: 2012

A recent trend in DNA nanotechnology consists of the assembly of architectures with dynamic properties that can be regulated by employing external stimuli. Reversible processes are important for implementing molecular motion into DNA architectures as they allow for the regeneration of the original state. Here we describe two different approaches for the reversible switching of a double-stranded DNA rotaxane architecture from a stationary pseudorotaxane mode into a state with movable components. Both states only marginally differ in their respective topologies but their mechanical properties are fundamentally different. In the two approaches, the switching operation is based on strand-displacement reactions. One of them employs toehold-extended oligodeoxynucleotides whereas in the other one the switching is achieved by light-irradiation. In both cases, multiple back and forth switching between the stationary and the mobile states was achieved in nearly quantitative fashion. The ability to reversibly operate mechanical motion in an interlocked DNA nanostructure opens exciting new avenues in DNA nanotechnology. © 2012 American Chemical Society.


PubMed | Howard Hughes Medical Institute and LIMES Institute
Type: | Journal: eLife | Year: 2016

NeuromedinU is a potent regulator of food intake and activity in mammals. In


News Article | February 3, 2016
Site: phys.org

Light microscopy image of a live Drosophila that was unable to produce enough growth factor idgf6 due to a genetic modification. As a result, defects can be seen in the respiratory organ as well as in the chitinous shell. Credit: Dr. Matthias Behr With their chitinous shells, insects seem almost invulnerable – but like Achilles' heel in Greek mythology, their impressive armor can still be attacked. Researchers at the universities of Bonn and Leipzig studied fruit flies (Drosophila) and discovered the molecular processes that are able to break through this protective casing. The enzyme chitinase 2 and growth factor idgf6 are especially important in correctly forming the insects' shells. These findings are relevant for fighting parasites, and will be published in the professional journal Scientific Reports. The same things that work with fruit flies (Drosophila) – one of developmental biologists' favorite animals to study – can generally also be applied to other insects. The deactivation of chitinase 2 and/or idgf6 genes results in a fragile shell that does not support adequate protection for larva of fruit flies and very likely other insects such as mosquitos. "Pathogens can then easily infiltrate the animals, and they usually die during the larval stage," says Assistant Professor Dr. Matthias Behr, who transferred from the Life & Medical Sciences (LIMES) Institute at his alma mater in Bonn to the Sächsische Inkubator für die klinische Translation (SIKT) at the University of Leipzig. The project was financed with funding from Special Research Area 645 at the University of Bonn. The current discovery offers completely new starting points for keeping agricultural parasites as well as dangerous disease-carrying insects in check. The enzyme chitinase 2 and growth factor idgf6 are essential for shell formation in nearly all insects, as well as in arthropods like crabs and spiders. "However, there are minor species-related differences that could allow us to develop tailor-made inhibitors that will prevent proper development of the chitinous shell in certain species," says first author Yanina-Yasmin Pesch from the LIMES Institute at the University of Bonn. Specially developed substances could be used to attack the chitinous covering of one arthropod species while leaving other species unharmed. Dr. Behr names two examples of possible applications: the spotted-wing drosophila (Drosophila suzukii) that recently migrated to Germany, and the new Zika virus pathogen. The spotted-wing drosophila causes enormous damage for the agricultural industry because it attacks a large volume of ripening fruit. The Zika virus is transmitted to people through mosquito bites. This virus is suspected of causing birth defects in Brazil, among other places. The researchers hope their discovery will make it easier to fight these kinds of dangerous insects in the future. The researchers from the universities of Bonn and Leipzig, as well as from the Max Planck Institute of Biophysical Chemistry in Göttingen, turned up one other surprising find: "Until now, scientists assumed that chitinase 2 was a degradation enzyme," reports Pesch. "But surprisingly, it has now been found that the enzyme is essential in forming the chitinous shell." When the protective casing is being created, chitinase shortens the chitin to the right length. The precisely tailored components are then combined with other materials to build the shell. As the team of researchers already showed in a previous study, the "Obstructor-A" protein plays a key role here. Like a construction-site manager, it makes sure that various building materials are added to the protective shell in the right places. "Step by step, our research is revealing molecular details about the insects' Achilles heel," says Dr. Behr. More information: Yanina-Yasmin Pesch et al. Chitinases and Imaginal disc growth factors organize the extracellular matrix formation at barrier tissues in insects, Scientific Reports (2016). DOI: 10.1038/srep18340


News Article | December 16, 2016
Site: www.eurekalert.org

Dendritic cells represent an important component of the immune system: they recognize and engulf invaders, which subsequently triggers a pathogen-specific immune response. Scientists of the University Hospital Erlangen of the Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and the LIMES (Life and Medical Sciences) Institute of the University of Bonn gained substantial knowledge of human dendritic cells, which might contribute to the development of immune therapies in the future. The results were recently published in the Journal Science Immunology. Dendritic cells - their name is derived from the large amount of dendrites on their cell surface - populate most parts of the human body. There they act as guards by recognizing, engulfing, and processing foreign pathogens. Finally, those dendritic cells migrate to nearby lymph nodes, where they interact with other immune cells to trigger a pathogen-specific immune response. Consequently, dendritic cells play an important role within the complex immune system. In recent years, it became evident that in the mouse dendritic cells are composed of different subtypes, which differ in function and distribution across the body. In contrast, less was known about the corresponding situation in humans. Recently, Dr. Gordon Heidkamp and Prof. Dr. Diana Dudziak from the University Hospital Erlangen performed a global study, which, for the first time, systematically characterized dendritic cells in different human organs such as blood, spleen, thymus, tonsils, bone marrow, cord blood. Using 16-color flow cytometry, they detected different dendritic cell subtypes, determined their distribution across the various organs and identified important cell surface proteins. As a result, the scientists revealed that the surface profiles of dendritic cells of the same subtype are constant throughout the different tissues. Additionally, the scientists from Erlangen isolated dendritic cells from human blood, spleen, and thymus and analyzed their genetic information in the form of ribonucleic acid (RNA). The complex data analysis was performed in close collaboration with Jil Sander and Prof. Dr. Joachim L. Schultze from the LIMES Institute of the University of Bonn. Using innovative methods, for example Cibersort analysis, they were able to imposingly demonstrate that the different subtypes share a constant profile, regardless of their initial location. Prof. Dr. Schultze: "In contrast, our data further demonstrate that within non-lymphatic organs such as lungs and skin, tissue-specific signals have a higher impact on the transcriptional output of dendritic cells." According to these recently published findings and due to the special characteristics of dendritic cells, the scientists expect substantial impacts on the therapy of immune diseases as well as on the development of new approaches to treat tumors. Prof. Dudziak summarizes: "There is evidence that dendritic cells might play a crucial role for the development of innovative therapies targeting the immune system. Our results help to understand the fundamental characteristics of dendritic cells." The study was conducted in a close collaboration between Dr. Gordon Heidkamp and Prof. Dr. Diana Dudziak from the University Hospital Erlangen and Jil Sander and Prof. Dr. Joachim L. Schultze from the LIMES Institute of the University of Bonn. The latter are members of the excellence cluster ImmunoSensation. In total, 31 scientists were involved in this project, located in Erlangen, Bonn, Kiel, Bamberg, Augsburg, Frankfurt, and Singapore. Publication: Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment, „Science Immunology"

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