Max Planck Institute For Experimentelle Medizin

Göttingen, Germany

Max Planck Institute For Experimentelle Medizin

Göttingen, Germany
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Weston M.,Baylor College of Medicine | Nehring R.,Baylor College of Medicine | Wojcik S.,Max Planck Institute For Experimentelle Medizin | Rosenmund C.,Baylor College of Medicine | Rosenmund C.,Charité - Medical University of Berlin
Neuron | Year: 2011

Vesicular glutamate transporters (VGLUTs) are essential for filling synaptic vesicles with glutamate and mammals express three VGLUT isoforms (VGLUT1-3) with distinct spatiotemporal expression patterns. Here, we find that neurons expressing VGLUT1 have lower release probability and less short-term depression than neurons expressing VGLUT2 or VGLUT3. Investigation of the underlying mechanism identified endophilin A1 as a positive regulator of exocytosis whose expression levels are positively correlated with release efficiency and showed that the differences in release efficiency between VGLUT1- and VGLUT2-expressing neurons are due to VGLUT1's ability to bind endophilin A1 and inhibit endophilin-induced enhancement of release probability. © 2011 Elsevier Inc.


Tognatta R.,University of Bonn | Sun W.,University of Bonn | Goebbels S.,Max Planck Institute For Experimentelle Medizin | Nave K.-A.,Max Planck Institute For Experimentelle Medizin | And 4 more authors.
GLIA | Year: 2017

NG2 expressing oligodendroglial precursor cells are ubiquitous in the central nervous system and the only cell type cycling throughout life. Previous fate mapping studies have remained inconsistent regarding the question whether NG2 cells are capable of generating certain types of neurons. Here, we use CNP-Cre mice to map the fate of a sub-population of NG2 cells assumed to be close to differentiation. When crossing these mice with the ROSA26/YFP Cre-reporter line we discovered large numbers of reporter-expressing pyramidal neurons in the piriform and dorsal cortex. In contrast, when using Z/EG reporter mice to track the fate of Cnp-expressing NG2 cells only oligodendroglial cells were found reporter positive. Using BrdU-based birth dating protocols and inducible NG2CreER:ROSA26/YFP mice we show that YFP positive neurons are generated from radial glial cells and that these radial glial cells display temporary and low level activity of certain oligodendroglial genes sufficient to recombine the Cre-inducible reporter gene in ROSA26/YFP but not in Z/EG mice. Taken together, we did not obtain evidence for generation of neurons from NG2 cells. Our results suggest that with an appropriate reporter system Cnp activity can be used to define a proliferative subpopulation of NG2 cells committed to generate oligodendrocytes. However, the strikingly different results obtained from ROSA26/YFP versus Z/EG mice demonstrate that the choice of Cre-reporter line can be of crucial importance for fate mapping studies and other applications of the Cre-lox technology. GLIA 2017;65:342–359. © 2016 Wiley Periodicals, Inc.


Liu Y.,Saarland University | Schirra C.,Saarland University | Edelmann L.,Saarland University | Matti U.,Saarland University | And 7 more authors.
Journal of Cell Biology | Year: 2010

Priming of large dense-core vesicles (LDCVs) is a Ca2+-dependent step by which LDCVs enter a release-ready pool, involving the formation of the soluble N-ethyl-maleimide sensitive fusion protein attachment protein (SNAP) receptor complex consisting of syntaxin, SNAP-25, and synaptobrevin. Using mice lacking both isoforms of the calcium-dependent activator protein for secretion (CAPS), we show that LDCV priming in adrenal chromaffin cells entails two distinct steps. CAPS is required for priming of the readily releasable LDCV pool and sustained secretion in the continued presence of high Ca2+ concentrations. Either CAPS1 or CAPS2 can rescue secretion in cells lacking both CAPS isoforms. Furthermore, the deficit in the readily releasable LDCV pool resulting from CAPS deletion is reversed by a constitutively open form of syntaxin but not by Munc13-1, a priming protein that facilitates the conversion of syntaxin to the open conformation. Our data indicate that CAPS functions downstream of Munc13s but also interacts functionally with Munc13s in the LDCV-priming process. © 2010 Liu et al.


Kolodziejczyk K.,University College London | Saab A.S.,Max Planck Institute For Experimentelle Medizin | Nave K.-A.,Max Planck Institute For Experimentelle Medizin | Attwell D.,University College London
F1000 Biology Reports | Year: 2010

The function of glutamate receptors on oligodendrocytes and their precursor cells is poorly understood, with their only clear action being to damage these cells in pathological conditions. Here we review recent studies of glutamate signalling to oligodendrocyte lineage cells, and explore what its physiological function may be. © 2010 Faculty of 1000 Ltd.


Mutations in the enzyme superoxide dismutase-1 (SOD1) cause hereditary variants of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). The pathophysiology of the disease is non-cell-autonomous: neurotoxicity is derived not only from mutant motor neurons but also from mutant neighbouring non-neuronal cells. In particular, microglia contribute to disease progression. By investigating acute lesions of spinal cord white matter in anaesthetised mice with fluorescently labelled microglia and axons using in vivo 2-photon laser-scanning microscopy (2P-LSM), we identified the messenger nitric oxide (NO) as a modulator of activated microglia. Subsequently, we investigated the role of microglia-related neuroinflammation in the affected lateral spinal cord of the ALS-linked transgenic SOD1 G93A mice. Different phases of microglia-mediated inflammation were observed: highly reactive microglial cells in preclinical stages and morphologically transformed ameboid microglia that have lost their function of tissue surveillance and injury-directed response in clinical stages. In another study, we observed rapid morphological reactions of mutant astroglial cells towards laser-induced axonal transection. Finally, we began to investigate the effect of methylene blue as an inhibitor of the NO pathway on microglia-mediated inflammation in affected motor parts of the spinal cord. An understanding of the pathomechanisms of degenerative processes in the spinal cord will be a prerequisite to develop efficient therapies for ALS. © Georg Thieme Verlag KG Stuttgart · New York.


Hartung F.,Max Planck Institute For Experimentelle Medizin | Stuhmer W.,Max Planck Institute For Experimentelle Medizin | Pardo L.A.,Max Planck Institute For Experimentelle Medizin
Molecular Cancer | Year: 2011

Background: The search for strategies to target ion channels for therapeutic applications has become of increasing interest. Especially, the potassium channel KV10.1 (Ether-á-go-go) is attractive as target since this surface protein is virtually not detected in normal tissue outside the central nervous system, but is expressed in approximately 70% of tumors from different origins.Methods: We designed a single-chain antibody against an extracellular region of KV10.1 (scFv62) and fused it to the human soluble TRAIL. The KV10.1-specific scFv62 antibody -TRAIL fusion protein was expressed in CHO-K1 cells, purified by chromatography and tested for biological activity.Results: Prostate cancer cells, either positive or negative for KV10.1 were treated with the purified construct. After sensitization with cytotoxic drugs, scFv62-TRAIL induced apoptosis only in KV10.1-positive cancer cells, but not in non-tumor cells, nor in tumor cells lacking KV10.1 expression. In co-cultures with KV10.1-positive cancer cells the fusion protein also induced apoptosis in bystander KV10.1-negative cancer cells, while normal prostate epithelial cells were not affected when present as bystander.Conclusions: KV10.1 represents a novel therapeutic target for cancer. We could design a strategy that selectively kills tumor cells based on a KV10.1-specific antibody. © 2011 Hartung et al; licensee BioMed Central Ltd.


De Queiroz F.M.,Max Planck Institute For Experimentelle Medizin | Sanchez A.,Max Planck Institute For Experimentelle Medizin | Agarwal J.R.,Max Planck Institute For Experimentelle Medizin | Stuhmer W.,Max Planck Institute For Experimentelle Medizin | Pardo L.A.,Max Planck Institute For Experimentelle Medizin
Molecular Biology Reports | Year: 2012

Transfection has become an everyday technique widely used for functional studies in living cells. The choice of the particular transfection method is usually determined by its efficiency and toxicity, and possible functional consequences specific to the method used are normally overlooked. We describe here that nucleofection, a method increasingly used because of its convenience and high efficiency, increases the metabolic rate of some cancer cells, which can be misleading when used as a measure of proliferation. Moreover, nucleofection can alter the subcellular expression pattern of the transfected protein. These undesired effects are independent of the transfected nucleic acid, but depend on the particular cell line used. Therefore, the interpretation of functional data using this technology requires further controls and caution. © Springer Science+Business Media B.V. 2011.


Eckstein F.,Max Planck Institute For Experimentelle Medizin
Nucleic Acid Therapeutics | Year: 2014

Phosphorothioates have found their usefulness in the general area of oligonucleotide therapeutic applications. Initially this modification was introduced into the antisense methodology because of the nuclease resistance of the phosphorothioate linkage in comparison with that of the phosphate linkage. However, as experimental data accumulated, it was detected that this chemical modification also facilitates cellular uptake and bioavailibity in vivo. Thus, today the majority of therapeutic oligonucleotides contain this modification. This review will discuss the historical development of this modification and present some of its chemical properties where they differ from those of the phosphate group. The antisense application will be discussed in the original context with cleavage of the target mRNA, but other target RNAs such as microRNAs and long noncoding RNAs will also be covered. It continues with applications where the target RNA should not be cleaved. A brief presentation of decoy oligonucleotides will be included, as well as some miscellaneous applications. Cellular uptake is a crucial step for oligonucleotides to reach their target and will be briefly reviewed. Lastly, a most surprising recent observation is the presence of phosphorothioate groups in bacterial DNA where functions still remain to be fully determined. © Copyright 2014, Mary Ann Liebert, Inc. 2014.


Schizophrenias are diagnosed purely clinically. The biological basis for this clinical entity is still fully unknown. Genetic studies have revealed some interesting hints but have not led to the identification of actual disease genotypes. On the contrary, it has become more and more probable that widely differing genotype constellations together with manifold environmental factors can trigger schizophrenia according to the motto "many roads lead to Rome..o". Thus, new strategies that allow a better insight into complex genotype-phenotype relationships, e. g. PGAS (phenotype-based genetic associations studies) are urgently needed. PGAS became possible on the basis of the GRAS data collection, the as yet largest worldwide phenotypical databank of schizophrenic patients. First PGAS proof-of-concept results on cognition or development-relevant genes are already available. © Georg Thieme Verlag KG Stuttgart, New York.


PubMed | Max Planck Institute For Experimentelle Medizin
Type: Historical Article | Journal: Nucleic acid therapeutics | Year: 2014

Phosphorothioates have found their usefulness in the general area of oligonucleotide therapeutic applications. Initially this modification was introduced into the antisense methodology because of the nuclease resistance of the phosphorothioate linkage in comparison with that of the phosphate linkage. However, as experimental data accumulated, it was detected that this chemical modification also facilitates cellular uptake and bioavailibity in vivo. Thus, today the majority of therapeutic oligonucleotides contain this modification. This review will discuss the historical development of this modification and present some of its chemical properties where they differ from those of the phosphate group. The antisense application will be discussed in the original context with cleavage of the target mRNA, but other target RNAs such as microRNAs and long noncoding RNAs will also be covered. It continues with applications where the target RNA should not be cleaved. A brief presentation of decoy oligonucleotides will be included, as well as some miscellaneous applications. Cellular uptake is a crucial step for oligonucleotides to reach their target and will be briefly reviewed. Lastly, a most surprising recent observation is the presence of phosphorothioate groups in bacterial DNA where functions still remain to be fully determined.

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