FMP Publications

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

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References
Liquid storage of boar semen: Current and future perspectives on the use of cationic antimicrobial peptides to replace antibiotics in semen extenders
Schulze(*), M., Dathe, M., Waberski(*), D.; Müller(*), K.
Theriogenology, 85:39-46
(2016)

Tags: Peptide-Lipid-Interaction/ Peptide Transport (Dathe)

Abstract: Antibiotics are of great importance in boar semen extenders to ensure long shelf life of spermatozoa and to reduce transmission of pathogens into the female tract. However, the use of antibiotics carries a risk of developing resistant bacterial strains in artificial insemination laboratories and their spread via artificial insemination. Development of multiresistant bacteria is a major concern if mixtures of antibiotics are used in semen extenders. Minimal contamination prevention techniques and surveillance of critical hygiene control points proved to be efficient in reducing bacterial load and preventing development of antibiotic resistance. Nevertheless, novel antimicrobial concepts are necessary for efficient bacterial control in extended boar semen with a minimum risk of evoking antibiotic resistance. Enhanced efforts have been made in recent years in the design and use of antimicrobial peptides (AMPs) as alternatives to conventional antibiotics. The male genital tract harbors a series of endogenic substances with antimicrobial activity and additional functions relevant to the fertilization process. However, exogenic AMPs often exert dose- and time-dependent toxic effects on mammalian spermatozoa. Therefore, it is important that potential newly designed AMPs have only minor impacts on eukaryotic cells. Recently, synthetic magainin derivatives and cyclic hexapeptides were tested for their application in boar semen preservation. Bacterial selectivity, proteolytic stability, thermodynamic resistance, and potential synergistic interaction with conventional antibiotics propel predominantly cyclic hexapeptides into highly promising, leading candidates for further development in semen preservation. The time scale for the development of resistant pathogens cannot be predicted at this moment.

Current Status: Site-Specific Antibody Drug Conjugates
Schumacher, D., Hackenberger, C. P., Leonhardt(*), H.; Helma(*), J.
Journal of clinical immunology, 36 Suppl 1:100-107
(2016)

Tags: Chemical Biology II (Hackenberger)

Abstract: Antibody drug conjugates (ADCs), a promising class of cancer biopharmaceuticals, combine the specificity of therapeutic antibodies with the pharmacological potency of chemical, cytotoxic drugs. Ever since the first ADCs on the market, a plethora of novel ADC technologies has emerged, covering as diverse aspects as antibody engineering, chemical linker optimization and novel conjugation strategies, together aiming at constantly widening the therapeutic window for ADCs. This review primarily focuses on novel chemical and biotechnological strategies for the site-directed attachment of drugs that are currently validated for 2nd generation ADCs to promote conjugate homogeneity and overall stability.

Lysosomal Dysfunction Caused by Cellular Accumulation of Silica Nanoparticles
Schütz, I., Lopez-Hernandez, T., Gao(*), Q., Puchkov, D., Jabs, S., Nordmeyer(*), D., Schmudde(*), M., Rühl(*), E., Graf(*), C. M.; Haucke, V.
J Biol Chem, 291:14170-14184
(2016)

Tags: Molecular Pharmacology and Cell Biology (Haucke), Physiology and Pathology of Ion Transport (Jentsch), Cellular Imaging (Wiesner, Puchkov)

Abstract: Nanoparticles (NPs) are widely used as components of drugs or cosmetics and hold great promise for biomedicine, yet their effects on cell physiology remain poorly understood. Here we demonstrate that clathrin-independent dynamin 2-mediated caveolar uptake of surface-functionalized silica nanoparticles (SiNPs) impairs cell viability due to lysosomal dysfunction. We show that internalized SiNPs accumulate in lysosomes resulting in inhibition of autophagy-mediated protein turnover and impaired degradation of internalized epidermal growth factor, whereas endosomal recycling proceeds unperturbed. This phenotype is caused by perturbed delivery of cargo via autophagosomes and late endosomes to SiNP-filled cathepsin B/L-containing lysosomes rather than elevated lysosomal pH or altered mTOR activity. Given the importance of autophagy and lysosomal protein degradation for cellular proteostasis and clearance of aggregated proteins, these results raise the question of beneficial use of NPs in biomedicine and beyond.

KCNQ Potassium Channels Modulate Sensitivity of Skin Down-hair (D-hair) Mechanoreceptors
Schütze, S., Orozco, I. J.; Jentsch, T. J.
J Biol Chem, 291:5566-5575
(2016)

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: M-current-mediating KCNQ (Kv7) channels play an important role in regulating the excitability of neuronal cells, as highlighted by mutations in Kcnq2 and Kcnq3 that underlie certain forms of epilepsy. In addition to their expression in brain, KCNQ2 and -3 are also found in the somatosensory system. We have now detected both KCNQ2 and KCNQ3 in a subset of dorsal root ganglia neurons that correspond to D-hair Adelta-fibers and demonstrate KCNQ3 expression in peripheral nerve endings of cutaneous D-hair follicles. Electrophysiological recordings from single D-hair afferents from Kcnq3(-/-) mice showed increased firing frequencies in response to mechanical ramp-and-hold stimuli. This effect was particularly pronounced at slow indentation velocities. Additional reduction of KCNQ2 expression further increased D-hair sensitivity. Together with previous work on the specific role of KCNQ4 in rapidly adapting skin mechanoreceptors, our results show that different KCNQ isoforms are specifically expressed in particular subsets of mechanosensory neurons and modulate their sensitivity directly in sensory nerve endings.

Semi-synthesis of a tag-free O-GlcNAcylated tau protein by sequential chemoselective ligation
Schwagerus, S., Reimann, O., Despres(*), C., Smet-Nocca(*), C.; Hackenberger, C. P.
J Pept Sci, 22:327-333
(2016)

Tags: Chemical Biology II (Hackenberger)

Abstract: In this paper, the first semi-synthesis of the Alzheimer-relevant tau protein carrying an O-GlcNAcylation is demonstrated by using sequential chemoselective ligation. The 52-amino acid C-terminus of tau was obtained by native chemical ligation between two synthetic peptide fragments, one carrying the O-GlcNAc moiety on Ser400, which has recently been demonstrated to inhibit tau phosphorylation and to hinder tau oligomerization, and the other equipped with a photocleavable biotin handle. After desulfurization to deliver a native alanine at the ligation junction, the N-terminal cysteine was unmasked, and the peptide was further used for expressed protein ligation to generate the full-length tau protein, which was purified by a photocleavable biotin tag. We thus provide a synthetic route to obtain a homogenous tag-free O-GlcNAcylated tau protein that can further help to elucidate the significance of posttranslational modification on the tau protein and pave the way for evaluating possible drug targets in Alzheimer's disease. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd.

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.

The progressive ankylosis protein ANK facilitates clathrin- and adaptor-mediated membrane traffic at the trans-Golgi network-to-endosome interface
Seifert(*), W., Posor, Y., Schu(*), P., Stenbeck(*), G., Mundlos(*), S., Klaassen(*), S., Nürnberg(*), P., Haucke, V., Kornak(*), U.; Kühnisch(*), J.
Hum Mol Genet, 25:3836-3848
(2016)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Dominant or recessive mutations in the progressive ankylosis gene ANKH have been linked to familial chondrocalcinosis (CCAL2), craniometaphyseal dysplasia (CMD), mental retardation, deafness and ankylosis syndrome (MRDA). The function of the encoded membrane protein ANK in cellular compartments other than the plasma membrane is unknown. Here, we show that ANK localizes to the trans-Golgi network (TGN), clathrin-coated vesicles and the plasma membrane. ANK functionally interacts with clathrin and clathrin associated adaptor protein (AP) complexes as loss of either protein causes ANK dispersion from the TGN to cytoplasmic endosome-like puncta. Consistent with its subcellular localization, loss of ANK results in reduced formation of tubular membrane carriers from the TGN, perinuclear accumulation of early endosomes and impaired transferrin endocytosis. Our data indicate that clathrin/AP-mediated cycling of ANK between the TGN, endosomes, and the cell surface regulates membrane traffic at the TGN/endosomal interface. These findings suggest that dysfunction of Golgi-endosomal membrane traffic may contribute to ANKH-associated pathologies.

Septins As Modulators of Endo-Lysosomal Membrane Traffic
Song, K., Russo, G.; Krauss, M.
Frontiers in cell and developmental biology, 4:124
(2016)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Septins constitute a family of GTP-binding proteins, which assemble into non-polar filaments in a nucleotide-dependent manner. These filaments can be recruited to negatively charged membrane surfaces. When associated with membranes septin filaments can act as diffusion barriers, which confine subdomains of distinct biological functions. In addition, they serve scaffolding roles by recruiting cytosolic proteins and other cytoskeletal elements. Septins have been implicated in a large variety of membrane-dependent processes, including cytokinesis, signaling, cell migration, and membrane traffic, and several family members have been implicated in disease. However, surprisingly little is known about the molecular mechanisms underlying their biological functions. This review summarizes evidence in support of regulatory roles of septins during endo-lysosomal sorting, with a particular focus on phosphoinositides, which serve as spatial landmarks guiding septin recruitment to distinct subcellular localizations.

Modes and mechanisms of synaptic vesicle recycling
Soykan, T., Maritzen, T.; Haucke, V.
Curr Opin Neurobiol, 39:17-23
(2016)

Tags: Molecular Pharmacology and Cell Biology (Haucke), Membrane Traffic and Cell Motility (Maritzen)

Abstract: Neurotransmission requires the recycling of synaptic vesicles (SVs) to replenish the SV pool, clear release sites, and maintain presynaptic integrity. In spite of decades of research the modes and mechanisms of SV recycling remain controversial. The identification of clathrin-independent modes of SV recycling such as ultrafast endocytosis has added to the debate. Accumulating evidence further suggests that SV membrane retrieval and the reformation of functional SVs are separable processes. This may allow synapses to rapidly restore membrane surface area over a wide range of stimulations followed by slow reformation of release-competent SVs. One of the future challenges will be to pinpoint the exact mechanisms that link SV recycling modes to synaptic activity patterns at different synapses.

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