FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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References
Occludin controls HIV transcription in brain pericytes via regulation of SIRT-1 activation
Castro(*), V., Bertrand(*), L., Luethen(*), M., Dabrowski, S., Lombardi(*), J., Morgan(*), L., Sharova(*), N., Stevenson(*), M., Blasig, I. E.; Toborek(*), M.
FASEB J, 30:1234-1246
(2016)

Tags: Molecular Cell Physiology (Blasig, I.E.)

Abstract: HIV invades the brain early after infection; however, its interactions with the cells of the blood-brain barrier (BBB) remain poorly understood. Our goal was to evaluate the role of occludin, one of the tight junction proteins that regulate BBB functions in HIV infection of BBB pericytes. We provide evidence that occludin levels largely control the metabolic responses of human pericytes to HIV. Occludin in BBB pericytes decreased by 10% during the first 48 h after HIV infection, correlating with increased nuclear translocation of the gene repressor C-terminal-binding protein (CtBP)-1 and NFkappaB-p65 activation. These changes were associated with decreased expression and activation of the class III histone deacetylase sirtuin (SIRT)-1. Occludin levels recovered 96 h after infection, restoring SIRT-1 and reducing HIV transcription to 20% of its highest values. We characterized occludin biochemically as a novel NADH oxidase that controls the expression and activation of SIRT-1. The inverse correlation between occludin and HIV transcription was then replicated in human primary macrophages and differentiated monocytic U937 cells, in which occludin silencing resulted in 75 and 250% increased viral transcription, respectively. Our work shows that occludin has previously unsuspected metabolic properties and is a target of HIV infection, opening the possibility of designing novel pharmacological approaches to control HIV transcription.

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes
Hu(*), H., Haas(*), S. A., Chelly(*), J., Van Esch(*), H., Raynaud(*), M., de Brouwer(*), A. P., Weinert, S., Froyen(*), G., Frints(*), S. G., Laumonnier, F., Zemojtel(*), T., Love(*), M. I., Richard(*), H., Emde(*), A. K., Bienek(*), M., Jensen(*), C., Hambrock(*), M., Fischer(*), U., Langnick(*), C., Feldkamp(*), M., Wissink-Lindhout(*), W., Lebrun(*), N., Castelnau(*), L., Rucci(*), J., Montjean(*), R., Dorseuil(*), O., Billuart(*), P., Stuhlmann, T., Shaw(*), M., Corbett(*), M. A., Gardner(*), A., Willis-Owen(*), S., Tan(*), C., Friend(*), K. L., Belet(*), S., van Roozendaal(*), K. E., Jimenez-Pocquet(*), M., Moizard(*), M. P., Ronce(*), N., Sun(*), R., O'Keeffe(*), S., Chenna(*), R., van Bommel(*), A., Goke(*), J., Hackett(*), A., Field(*), M., Christie(*), L., Boyle(*), J., Haan(*), E., Nelson(*), J., Turner(*), G., Baynam(*), G., Gillessen-Kaesbach(*), G., Müller, U., Steinberger(*), D., Budny(*), B., Badura-Stronka(*), M., Latos-Bielenska(*), A., Ousager(*), L. B., Wieacker(*), P., Rodriguez Criado(*), G., Bondeson(*), M. L., Anneren(*), G., Dufke(*), A., Cohen(*), M., Van Maldergem(*), L., Vincent-Delorme(*), C., Echenne(*), B., Simon-Bouy(*), B., Kleefstra(*), T., Willemsen(*), M., Fryns(*), J. P., Devriendt(*), K., Ullmann(*), R., Vingron(*), M., Wrogemann(*), K., Wienker(*), T. F., Tzschach(*), A., van Bokhoven(*), H., Gecz(*), J., Jentsch, T. J., Chen(*), W., Ropers(*), H. H.; Kalscheuer(*), V. M.
Molecular psychiatry, 21:133-148
(2016)

Tags: Physiology and Pathology of Ion Transport (Jentsch

Abstract: X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Differentially Isotope-Labeled Nucleosomes To Study Asymmetric Histone Modification Crosstalk by Time-Resolved NMR Spectroscopy
Liokatis, S., Klingberg, R., Tan(*), S.; Schwarzer(*), D.
Angew Chem Int Ed Engl, 55:8262-8265
(2016)

Tags: In-Cell NMR (Selenko), Protein Chemistry (Schwarzer)

Abstract: Post-translational modifications (PTMs) of histones regulate chromatin structure and function. Because nucleosomes contain two copies each of the four core histones, the establishment of different PTMs on individual "sister" histones in the same nucleosomal context, that is, asymmetric histone PTMs, are difficult to analyze. Here, we generated differentially isotope-labeled nucleosomes to study asymmetric histone modification crosstalk by time-resolved NMR spectroscopy. Specifically, we present mechanistic insights into nucleosomal histone H3 modification reactions in cis and in trans, that is, within individual H3 copies or between them. We validated our approach by using the H3S10phK14ac crosstalk mechanism, which is mediated by the Gcn5 acetyltransferase. Moreover, phosphorylation assays on methylated substrates showed that, under certain conditions, Haspin kinase is able to produce nucleosomes decorated asymmetrically with two distinct types of PTMs.

Green tea reduces body fat via upregulation of neprilysin
Muenzner, M., Tappenbeck(*), N., Gembardt(*), F., Rülke, R., Furkert, J., Melzig(*), M. F., Siems, W. E., Brockmann(*), G. A.; Walther(*), T.
Int J Obes (Lond), 40:1850-1855
(2016)

Tags: Biochemical Neurobiology (Siems)

Abstract: BACKGROUND/OBJECTIVE: Consumption of green tea has become increasingly popular, particularly because of claimed reduction in body weight. We recently reported that animals with pharmacological inhibition (by candoxatril) or genetic absence of the endopeptidase neprilysin (NEP) develop an obese phenotype. We now investigated the effect of green tea extract (in drinking water) on body weight and body composition and the mediating role of NEP. SUBJECTS/METHODS: To elucidate the role of NEP in mediating the beneficial effects of green tea extract, 'Berlin fat mice' or NEP-deficient mice and their age- and gender-matched wild-type controls received the extract in two different doses (300 or 600 mg kg-1 body weight per day) in the drinking water. RESULTS: In 'Berlin fat mice', 51 days of green tea treatment did not only prevent fat accumulation (control: day 0: 30.5% fat, day 51: 33.1%; NS) but also reduced significant body fat (green tea: day 0: 27.8%, day 51: 20.9%, P<0.01) and body weight below the initial levels. Green tea reduced food intake. This was paralleled by a selective increase in peripheral (in kidney 17%, in intestine 92%), but not central NEP expression and activity, leading to downregulation of orexigens (like galanin and neuropeptide Y (NPY)) known to be physiological substrates of NEP. Consequently, in NEP-knockout mice, green tea extract failed to reduce body fat/weight. CONCLUSIONS: Our data generate experimental proof for the assumed effects of green tea on body weight and the key role for NEP in such process, and thus open a new avenue for the treatment of obesity.

De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females
Palmer(*), E. E., Stuhlmann, T., Weinert, S., Haan(*), E., Van Esch(*), H., Holvoet(*), M., Boyle(*), J., Leffler(*), M., Raynaud(*), M., Moraine(*), C., van Bokhoven(*), H., Kleefstra(*), T., Kahrizi(*), K., Najmabadi(*), H., Ropers(*), H. H., Delgado(*), M. R., Sirsi(*), D., Golla(*), S., Sommer(*), A., Pietryga(*), M. P., Chung(*), W. K., Wynn(*), J., Rohena(*), L., Bernardo(*), E., Hamlin(*), D., Faux(*), B. M., Grange(*), D. K., Manwaring(*), L., Tolmie(*), J., Joss(*), S., Cobben(*), J. M., Duijkers(*), F. A., Goehringer(*), J. M., Challman(*), T. D., Hennig(*), F., Fischer(*), U., Grimme(*), A., Suckow(*), V., Musante(*), L., Nicholl(*), J., Shaw(*), M., Lodh(*), S. P., Niu(*), Z., Rosenfeld(*), J. A., Stankiewicz(*), P., Jentsch, T. J., Gecz(*), J., Field(*), M.; Kalscheuer(*), V. M.
Molecular psychiatry,
(2016)

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.Molecular Psychiatry advance online publication, 23 August 2016; doi:10.1038/mp.2016.135.

Effects of Halide Ions on the Carbamidocyclophane Biosynthesis in Nostoc sp. CAVN2
Preisitsch(*), M., Heiden(*), S. E., Beerbaum, M., Niedermeyer(*), T. H., Schneefeld(*), M., Herrmann(*), J., Kumpfmüller(*), J., Thürmer(*), A., Neidhardt(*), I., Wiesner(*), C., Daniel(*), R., Müller(*), R., Bange(*), F. C., Schmieder, P., Schweder(*), T.; Mundt(*), S.
Mar Drugs, 14:21
(2016)

Tags: Solution NMR (Schmieder)

Abstract: In this study, the influence of halide ions on [7.7]paracyclophane biosynthesis in the cyanobacterium Nostoc sp. CAVN2 was investigated. In contrast to KI and KF, supplementation of the culture medium with KCl or KBr resulted not only in an increase of growth but also in an up-regulation of carbamidocyclophane production. LC-MS analysis indicated the presence of chlorinated, brominated, but also non-halogenated derivatives. In addition to 22 known cylindrocyclophanes and carbamidocyclophanes, 27 putative congeners have been detected. Nine compounds, carbamidocyclophanes M-U, were isolated, and their structural elucidation by 1D and 2D NMR experiments in combination with HRMS and ECD analysis revealed that they are brominated analogues of chlorinated carbamidocyclophanes. Quantification of the carbamidocyclophanes showed that chloride is the preferably utilized halide, but incorporation is reduced in the presence of bromide. Evaluation of the antibacterial activity of 30 [7.7]paracyclophanes and related derivatives against selected pathogenic Gram-positive and Gram-negative bacteria exhibited remarkable effects especially against methicillin- and vancomycin-resistant staphylococci and Mycobacterium tuberculosis. For deeper insights into the mechanisms of biosynthesis, the carbamidocyclophane biosynthetic gene cluster in Nostoc sp. CAVN2 was studied. The gene putatively coding for the carbamoyltransferase has been identified. Based on bioinformatic analyses, a possible biosynthetic assembly is discussed.

A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K(+) Channels
Schewe(*), M., Nematian-Ardestani(*), E., Sun, H., Musinszki(*), M., Cordeiro(*), S., Bucci(*), G., de Groot(*), B. L., Tucker(*), S. J., Rapedius(*), M.; Baukrowitz(*), T.
Cell, 164:937-949
(2016)

Tags: Computational Chemistry and Protein Design (Kühne)

Abstract: Two-pore domain (K2P) K(+) channels are major regulators of excitability that endow cells with an outwardly rectifying background "leak" conductance. In some K2P channels, strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage-sensing domain. Here, we show voltage-dependent gating is common to most K2P channels and that this voltage sensitivity originates from the movement of three to four ions into the high electric field of an inactive selectivity filter. Overall, this ion-flux gating mechanism generates a one-way "check valve" within the filter because outward movement of K(+) induces filter opening, whereas inward movement promotes inactivation. Furthermore, many physiological stimuli switch off this flux gating mode to convert K2P channels into a leak conductance. These findings provide insight into the functional plasticity of a K(+)-selective filter and also refine our understanding of K2P channels and the mechanisms by which ion channels can sense voltage.

Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus
Stempel(*), A. V., Stumpf(*), A., Zhang(*), H. Y., Ozdogan(*), T., Pannasch(*), U., Theis(*), A. K., Otte(*), D. M., Wojtalla(*), A., Racz(*), I., Ponomarenko, A., Xi(*), Z. X., Zimmer(*), A.; Schmitz(*), D.
Neuron, 90:795-809
(2016)

Tags: Behavioral Neurodynamics (Korotkova/Ponomarenko)

Abstract: Endocannabinoids (eCBs) exert major control over neuronal activity by activating cannabinoid receptors (CBRs). The functionality of the eCB system is primarily ascribed to the well-documented retrograde activation of presynaptic CB1Rs. We find that action potential-driven eCB release leads to a long-lasting membrane potential hyperpolarization in hippocampal principal cells that is independent of CB1Rs. The hyperpolarization, which is specific to CA3 and CA2 pyramidal cells (PCs), depends on the activation of neuronal CB2Rs, as shown by a combined pharmacogenetic and immunohistochemical approach. Upon activation, they modulate the activity of the sodium-bicarbonate co-transporter, leading to a hyperpolarization of the neuron. CB2R activation occurred in a purely self-regulatory manner, robustly altered the input/output function of CA3 PCs, and modulated gamma oscillations in vivo. To conclude, we describe a cell type-specific plasticity mechanism in the hippocampus that provides evidence for the neuronal expression of CB2Rs and emphasizes their importance in basic neuronal transmission.

Young, active and well-connected: adult-born neurons in the zebra finch are activated during singing
Tokarev(*), K., Boender(*), A. J., Classen, G. A.; Scharff(*), C.
Brain Struct Funct, 221:1833-1843
(2016)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Neuronal replacement in the pallial song control nucleus HVC of adult zebra finches constitutes an interesting case of homeostatic plasticity; in spite of continuous addition and attrition of neurons in ensembles that code song elements, adult song remains remarkably invariant. New neurons migrate into HVC and later synapse with their target, arcopallial song nucleus RA (HVCRA). New HVCRA neurons respond to auditory stimuli (in anaesthetised animals), but whether and when they become functionally active during singing is unknown. We studied this, using 5-bromo-2'-deoxyuridine to birth-date neurons, combined with immunohistochemical detection of immediate-early gene (IEG) expression and retrograde tracer injections into RA to track connectivity. Interestingly, singing was followed by IEG expression in a substantial fraction of new neurons that were not retrogradely labelled from RA, suggesting a possible role in HVC-intrinsic network function. As new HVC neurons matured, the proportion of HVCRA neurons that expressed IEGs after singing increased significantly. Since it was previously shown that singing induces IEG expression in HVC also in deaf birds and that hearing song does not induce IEG expression in HVC, our data provide the first direct evidence that new HVC neurons are engaged in song motor behaviour.

An Alignment Medium for Measuring Residual Dipolar Couplings in Pure DMSO: Liquid Crystals from Graphene Oxide Grafted with Polymer Brushes
Zong(*), W., Li(*), G. W., Cao(*), J. M., Lei(*), X., Hu(*), M. L., Sun, H., Griesinger(*), C.; Tan(*), R. X.
Angew Chem Int Ed Engl, 55:3690-3693
(2016)

Tags: Computational Chemistry and Protein Design (Kühne)

Abstract: Residual dipolar couplings (RDCs) have attracted attention in light of their great impact on the structural elucidation of organic molecules. However, the effectiveness of RDC measurements is limited by the shortage of alignment media compatible with widely used organic solvents, such as DMSO. Herein, we present the first liquid crystal (LC) based alignment medium that is compatible with pure DMSO, thus enabling RDC measurements of polar and intermediate polarity molecules. The liquid crystals were obtained by grafting polymer brushes onto graphene oxide (GO) using free radical polymerization. The resulting new medium offers several advantages, such as absence of background signals, narrow line shapes, and tunable alignment. Importantly, this medium is compatible with pi-conjugated molecules. Moreover, sonication-induced fragmentation can reduce the size of GO sheets. The resulting anisotropic medium has moderate alignment strength, which is a prerequisite for an accurate RDC measurement.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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