FMP Publications

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

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References
Insight into the Modification of Polymeric Micellar and Liposomal Nanocarriers by Fluorescein-Labeled Lipids and Uptake-Mediating Lipopeptides
Draffehn(*), S., Eichhorst, J., Wiesner, B.; Kumke(*), M. U.
Langmuir, 32:6928-6939
(2016)

Tags: Cellular Imaging (Wiesner)

Abstract: Encapsulation of diagnostic and therapeutic compounds in transporters improves their delivery to the point of need. An even more efficient treatment of diseases can be achieved using carriers with targeting or protecting moieties. In the present work, we investigated micellar and liposomal nanocarriers modified with fluorescein, peptides, and polymers that are covalently bound to fatty acids or phospholipids to ensure a self-driven incorporation into the micelles or liposomes. First, we characterized the photophysics of the fluorescent probes in the absence and in the presence of nanocarriers. Changes in the fluorescence decay time, quantum yield, and intensity of a fluorescein-labeled fatty acid (fluorescein-labeled palmitic acid [fPA]) and a fluorescein-labeled lipopeptide (P2fA2) were found. By exploiting these changes, we investigated a lipopeptide (P2A2 as an uptake-mediating unit) in combination with different nanocarriers (micelles and liposomes) and determined the corresponding association constant Kass values, which were found to be very high. In addition, the mobility of fPA was exploited using fluorescence correlation spectroscopy (FCS) and fluorescence depolarization (FD) experiments to characterize the nanocarriers. Cellular uptake experiments with mouse brain endothelial cells provided information on the uptake behavior of liposomes modified by uptake-mediating P2A2 and revealed differences in the uptake behavior between pH-sensitive and pH-insensitive liposomes.

Interplay between redox and protein homeostasis
Feleciano, D. R., Arnsburg, K.; Kirstein, J.
Worm, 5:e1170273
(2016)

Tags: Proteostasis in Aging and Disease (Kirstein)

Abstract: The subcellular compartments of eukaryotic cells are characterized by different redox environments. Whereas the cytosol, nucleus and mitochondria are more reducing, the endoplasmic reticulum represents a more oxidizing environment. As the redox level controls the formation of intra- and inter-molecular disulfide bonds, the folding of proteins is tightly linked to its environment. The proteostasis network of each compartment needs to be adapted to the compartmental redox properties. In addition to chaperones, also members of the thioredoxin superfamily can influence the folding of proteins by regulation of cysteine reduction/oxidation. This review will focus on thioredoxin superfamily members and chaperones of C. elegans, which play an important role at the interface between redox and protein homeostasis. Additionally, this review will highlight recent methodological developments on in vivo and in vitro assessment of the redox state and their application to provide insights into the high complexity of redox and proteostasis networks of C. elegans.

Collapse of redox homeostasis during aging and stress
Feleciano, D. R.; Kirstein, J.
Mol Cell Oncol, 3:e1091060
(2016)

Tags: Proteostasis in Aging and Disease (Kirstein)

Abstract: Coordination of the protein homeostasis network and redox states in eukaryotic cells is crucial for cellular and organismal fitness. By employing endogenous in vivo redox sensors we demonstrate that the redox state of the ER and cytosol is subject to profound changes upon proteotoxic challenges and during aging.

Cellular strategies to cope with protein aggregation
Scior, A., Juenemann, K.; Kirstein, J.
Essays Biochem, 60:153-161
(2016)

Tags: Proteostasis in Aging and Disease (Kirstein)

Abstract: Nature has evolved several mechanisms to detoxify intracellular protein aggregates that arise upon proteotoxic challenges. These include the controlled deposition of misfolded proteins at distinct cellular sites, the protein disaggregation and refolding by molecular chaperones and/or degradation of misfolded and aggregated protein species by cellular clearance pathways. In this article, we discuss cellular the strategies of prokaroytes and eukaryotes to control protein aggregation.

Cellular strategies to cope with protein aggregation
Scior, A., Jünemann, K.; Kirstein, J.
In VanOostenHawle, P., editor, Volume 60 of Essays in Biochemistry
page 153-161.
Publisher: Portland Press Ltd, London
(2016)
OA-Link

Tags: Proteostasis in Aging and Disease (Kirstein)

Abstract: Nature has evolved several mechanisms to detoxify intracellular protein aggregates that arise upon proteotoxic challenges. These include the controlled deposition of misfolded proteins at distinct cellular sites, the protein disaggregation and refolding by molecular chaperones and/or degradation of misfolded and aggregated protein species by cellular clearance pathways. In this article, we discuss cellular the strategies of prokaroytes and eukaryotes to control protein aggregation.

Chemical fragment arrays for rapid druggability assessment
Aretz(*), J., Kondoh(*), Y., Honda(*), K., Anumala, U. R., Nazare, M., Watanabe(*), N., Osada(*), H.; Rademacher(*), C.
Chem Commun (Camb), 52:9067-9070
(2016)

Tags: Medicinal Chemistry (Nazare)

Abstract: Incorporation of early druggability assessment in the drug discovery process provides a means to prioritize target proteins for high-throughput screening. We present chemical fragment arrays as a method that is capable of determining the druggability of a given target with low protein and compound consumption, enabling rapid decision making during early phases of drug discovery.

The sclerostin-neutralizing antibody AbD09097 recognizes an epitope adjacent to sclerostin's binding site for the Wnt co-receptor LRP6
Boschert(*), V., Frisch(*), C., Back(*), J. W., van Pee(*), K., Weidauer(*), S. E., Muth(*), E. M., Schmieder, P., Beerbaum, M., Knappik(*), A., Timmerman(*), P.; Mueller(*), T. D.
Open biology, 6
(2016)

Tags: Solution NMR (Schmieder)

Abstract: The glycoprotein sclerostin has been identified as a negative regulator of bone growth. It exerts its function by interacting with the Wnt co-receptor LRP5/6, blocks the binding of Wnt factors and thereby inhibits Wnt signalling. Neutralizing anti-sclerostin antibodies are able to restore Wnt activity and enhance bone growth thereby presenting a new osteoanabolic therapy approach for diseases such as osteoporosis. We have generated various Fab antibodies against human and murine sclerostin using a phage display set-up. Biochemical analyses have identified one Fab developed against murine sclerostin, AbD09097 that efficiently neutralizes sclerostin's Wnt inhibitory activity. In vitro interaction analysis using sclerostin variants revealed that this neutralizing Fab binds to sclerostin's flexible second loop, which has been shown to harbour the LRP5/6 binding motif. Affinity maturation was then applied to AbD09097, providing a set of improved neutralizing Fab antibodies which particularly bind human sclerostin with enhanced affinity. Determining the crystal structure of AbD09097 provides first insights into how this antibody might recognize and neutralize sclerostin. Together with the structure-function relationship derived from affinity maturation these new data will foster the rational design of new and highly efficient anti-sclerostin antibodies for the therapy of bone loss diseases such as osteoporosis.

Intradomain Allosteric Network Modulates Calcium Affinity of the C-Type Lectin Receptor Langerin
Hanske(*), J., Aleksic(*), S., Ballaschk, M., Jurk(*), M., Shanina(*), E., Beerbaum, M., Schmieder, P., Keller(*), B. G.; Rademacher(*), C.
J Am Chem Soc, 138:12176-12186
(2016)

Tags: Solution NMR (Schmieder)

Abstract: Antigen uptake and processing by innate immune cells is crucial to initiate the immune response. Therein, the endocytic C-type lectin receptors serve as pattern recognition receptors, detecting pathogens by their glycan structures. Herein, we studied the carbohydrate recognition domain of Langerin, a C-type lectin receptor involved in the host defense against viruses such as HIV and influenza as well as bacteria and fungi. Using a combination of nuclear magnetic resonance and molecular dynamics simulations, we unraveled the molecular determinants underlying cargo capture and release encoded in the receptor architecture. Our findings revealed receptor dynamics over several time scales associated with binding and release of the essential cofactor Ca(2+) controlled by the coupled motions of two loops. Applying mutual information theory and site-directed mutagenesis, we identified an allosteric intradomain network that modulates the Ca(2+) affinity depending on the pH, thereby promoting fast ligand release.

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.

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.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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13125 Berlin, Germany
+4930 94793 - 100 
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info(at)fmp-berlin.de

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