Research Area F - Publications 2015
Chem. Sci.,7, 2347-2352, DOI: 10.1039/C5SC04084A
Chem. Sci., online article
G-protein coupled inwardly rectifying potassium (GIRK) channels are expressed throughout the human body and are an integral part of inhibitory signal transduction pathways. Upon binding of Gβγ subunits released from G-protein coupled receptors (GPCRs), GIRK channels open and reduce the activity of excitable cells via hyperpolarization. As such, they play a role ...
Engulfment pathways promote programmed cell death by enhancing the unequal segregation of apoptotic potential
Nature Communications, 6, Article number:10126, doi:10.1038/ncomms10126
Components of the conserved engulfment pathways promote programmed cell death in Caenorhabditis elegans (C. elegans) through an unknown mechanism. Here we report that the phagocytic receptor CED-1 mEGF10 is required for the formation of a dorsal–ventral gradient of CED-3 caspase activity within the mother of a cell programmed to die and an increase in the level ...
Comprehensive multilevel in vivo and in vitro analysis of heart rate fluctuations in mice by ECG telemetry and electrophysiology
Nature Protocols, 11, 61–86, doi:10.1038/nprot.2015.139
The normal heartbeat slightly fluctuates around a mean value; this phenomenon is called physiological heart rate variability (HRV). It is well known that altered HRV is a risk factor for sudden cardiac death. The availability of genetic mouse models makes it possible to experimentally dissect the mechanism of pathological changes in HRV and its relation to sudden ...
Nat. Prod. Rep., 33, 491-522, DOI: 10.1039/C5NP00096C
Nat. Prod. Rep., online article
Alkaloids account for some of the most beautiful and biologically active natural products. Although they are usually classified along biosynthetic criteria, they can also be categorized according to certain structural motifs. Amongst these, the α-tertiary amine (ATA), i.e. a tetrasubstituted carbon atom surrounded by three carbons and one nitrogen, is ...
Angew. Chem. 2015, 127, 1 – 6, DOI: 10.1002/ange.201506384
Inkretin-Mimetika sind auf dem besten Weg, sich zu einer tragenden Säule in der Typ-2-Diabetes-Behandlung zu entwickeln. Durch ihre Wirkung auf die Bauchspeicheldrüse und das Gehirn verstärken sie die Insulinsekretion, induzieren einen Gewichtsverlust und halten die Normoglykämie aufrecht. Allerdings wird die Inkretin-Therapie mit Nebenwirkungen wie Übelkeit und ...
ACS Chem. Neurosci., DOI: 10.1021/acschemneuro.5b00234
ACS Chem. Neurosci., online article
Retinal degenerative diseases can have many possible causes and are currently difficult to treat. As an alternative to therapies that require genetic manipulation or the implantation of electronic devices, photopharmacology has emerged as a viable approach to restore visual responses. Here, we present a new photopharmacological strategy that relies on a ...
Nature Neuroscience, doi:10.1038/nn.4137
Alzheimer's disease (AD) is associated with defects of synaptic connectivity. Such defects may not be restricted to local neuronal interactions but may extend to long-range brain activities, such as slow-wave oscillations that are particularly prominent during non–rapid eye movement (non-REM) sleep and are important for integration of information across distant ...
AGING, Vol 7, No 9 , pp 701-717
The inactivation of the LRPPRC gene, which has previously been associated with the neurodegenerative French Canadian Leigh Syndrome, results in a decrease in the production of mitochondria-encoded subunits of complex IV, thereby causing a reduction in complex IV activity. Previously we have shown that reducing complex IV activity triggers a compensatory and ...
Biochemistry, 54 (40), pp 6149–6152, DOI: 10.1021/acs.biochem.5b00986
The amyloid precursor protein (APP) is a single-span integral membrane protein whose C-terminal fragment C99 is cleaved within the transmembrane helix by γ-secretase. Cleavage produces various Aβ peptides that are linked to the etiology of Alzheimer’s disease. The transmembrane helix is known to homodimerize in a sequence-specific manner, and considerable ...
Corticotropin-Releasing Hormone Receptor Type 1 (CRHR1) Clustering with MAGUKs Is Mediated via Its C-Terminal PDZ Binding Motif
PLOS ONE, DOI:10.1371/journal.pone.0136768
The corticotropin-releasing hormone receptor type 1 (CRHR1) plays an important role in orchestrating neuroendocrine, behavioral, and autonomic responses to stress. To identify molecules capable of directly modulating CRHR1 signaling, we performed a yeast-two-hybrid screen using the C-terminal intracellular tail of the receptor as bait. We identified several ...
Nature Chemistry, doi:10.1038/nchem.2336
Epicolactone is a recently isolated fungal metabolite that is highly complex for its size, and yet racemic. With its array of quaternary stereocentres, high degree of functionalization and intricate polycyclic structure, it poses a considerable challenge to synthesis, a challenge that can be met by understanding its biosynthetic origin. If drawn in a certain way, ...
Nature Communications 6, Article number: 8076, doi:10.1038/ncomms9076
Nature Communications, online article
N-methyl-D-aspartate receptors (NMDARs) play a central role in synaptic plasticity, learning and memory, and are implicated in various neuronal disorders. We synthesized a diffusible photochromic glutamate analogue, azobenzene-triazole-glutamate (ATG), which is specific for NMDARs and functions as a photoswitchable agonist. ATG is inactive in its dark-adapted ...
PNAS, vol. 112, no. 36, 11377–11382, doi: 10.1073/pnas.1514209112
In vivo Ca2+ imaging of neuronal populations in deep cortical layers has remained a major challenge, as the recording depth of two-photon microscopy is limited because of the scattering and absorption of photons in brain tissue. A possible strategy to increase the imaging depth is the use of red-shifted fluorescent dyes, as scattering of photons is reduced at ...
Biochemistry, 54 (33), pp 5125–5135, DOI: 10.1021/acs.biochem.5b00495
Transmembrane (TM) helices of integral membrane proteins can facilitate strong and specific noncovalent protein–protein interactions. Mutagenesis and structural analyses have revealed numerous examples in which the interaction between TM helices of single-pass membrane proteins is dependent on a GxxxG or (small)xxx(small) motif. It is therefore tempting to use ...
Hum. Mol. Genet., 24 (19), 5486-5499, doi: 10.1093/hmg/ddv275
Mutations in the PDE6A gene can cause rod photoreceptors degeneration and the blinding disease retinitis pigmentosa (RP). While a number of pathogenic PDE6A mutations have been described, little is known about their impact on compound heterozygous situations and potential interactions of different disease-causing alleles. Here, we used a novel mouse model for the ...
Cell, Volume 162, Issue 2, p403–411, http://dx.doi.org/10.1016/j.cell.2015.06.049
Small molecules that interfere with microtubule dynamics, such as Taxol and the Vinca alkaloids, are widely used in cell biology research and as clinical anticancer drugs. However, their activity cannot be restricted to specific target cells, which also causes severe side effects in chemotherapy. Here, we introduce the photostatins, inhibitors that can be ...
Beilstein J. Org. Chem., 11, 1129–1135, doi:10.3762/bjoc.11.127
Aryl sulfonamides are a widely used drug class for the inhibition of carbonic anhydrases. In the context of our program of photochromic pharmacophores we were interested in the exploration of azobenzene-containing sulfonamides to block the catalytic activity of human carbonic anhydrase II (hCAII). Herein, we report the synthesis and in vitro evaluation of a small ...
Age-Dependent Levels of 5-Methyl-, 5-Hydroxymethyl-, and 5-Formylcytosine in Human and Mouse Brain Tissues
Angewandte Chemie International Edition 54, 1 – 5, DOI: 10.1002/anie.201502722
The absolute levels of 5-hydroxymethylcytosine (hmC) and 5-methylcytosine (mC) in human brain tissues at various ages were determined. Additionally, absolute levels of 5-formylcytosine (fC) in adult individuals and cytosine modification levels in sorted neurons were quantified. These data were compared with age-related fC, hmC, and mC levels in mouse brain ...
Journal of Molecular Medicine, Volume 93, Issue 9, pp 983-989, DOI 10.1007/s00109-015-1298-7
The transient receptor potential (TRPC) proteins form non-selective cation channels that are activated downstream of Gq-phospholipase C-coupled receptors. TRPC3, one of the seven members of the TRPC subfamily, combines functions of an unspecific ion channel and a signal transducer. In the mammalian brain, the expression of TRPC3 is highest in cerebellar Purkinje ...
Electroretinographic assessment of rod- and cone-mediated bipolar cell pathways using flicker stimuli in mice
Scientific Reports, 5, Article number: 10731, doi:10.1038/srep10731
Mouse full-field electroretinograms (ERGs) are dominated by responses of photoreceptors and depolarizing (ON-) bipolar cells, but not much of hyperpolarizing (OFF-) bipolar cells under conventional recording conditions. Here we investigate a novel ERG protocol in mice for functional assessment of the major ON- and OFF-bipolar cell pathways using flicker stimuli ...
cGMP/PKG Signaling Suppresses Inositol 1,4,5-Trisphosphate Receptor Phosphorylation and Promotes Endoplasmic Reticulum Stress in Photoreceptors of CNG Channel-Deficient Mice
THE JOURNAL OF BIOLOGICAL CHEMISTRY, VOL. 290, NO. 34, pp. 20880–20892, doi:10.1074/jbc.M115.641159
Photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. We have shown endoplasmic reticulum (ER) stress-associated apoptotic cone death and increased phosphorylation of the ER Ca2+ channel inositol ...
Nature Communications, online article
Fatty acids (FAs) are not only essential components of cellular energy storage and structure, but play crucial roles in signalling. Here we present a toolkit of photoswitchable FA analogues (FAAzos) that incorporate an azobenzene photoswitch along the FA chain. By modifying the FAAzos to resemble capsaicin, we prepare a series of photolipids targeting the ...
Neurology, online article
Objectives: To characterize phenotypes of T cells that accumulated in multiple sclerosis (MS) lesions, to compare the lesional T-cell receptor (TCR) repertoire of T-cell subsets to peripheral blood, and to identify paired α and β chains from single CD8+ T cells from an index patient who we followed for 18 years. Methods: We combined immunohistochemistry, laser ...
Trends in Biochemical Sciences, Volume 40, Issue 6, p318–327 DOI: http://dx.doi.org/10.1016/j.tibs.2015.04.001
Intramembrane proteolysis – cleavage of proteins within the plane of a membrane – is a widespread phenomenon that can contribute to the functional activation of substrates and is involved in several diseases. Although different families of intramembrane proteases have been discovered and characterized, we currently do not know how these enzymes discriminate ...
Angewandte Chemie International Edition, online article
A biomimetic total synthesis of santalin Y, a structurally complex but racemic natural product, is described. The key step is proposed to be a (3+2) cycloaddition of a benzylstyrene to a “vinylogous oxidopyrylium”, which is followed by an intramolecular Friedel–Crafts reaction. This cascade generates the unique oxafenestrane framework of the target molecule and ...
Cell Reports, online article
Ten-eleven translocation hydroxylases (TET1-3) oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). In neurons, increased 5hmC levels within gene bodies correlate positively with gene expression. The mechanisms controlling TET activity and 5hmC levels are poorly understood. In particular, it is not known how the neuronal TET3 isoform lacking a ...
The EMBO Journal, online article
The second messenger NAADP triggers Ca2+ release from endo-lysosomes. Although two-pore channels (TPCs) have been proposed to be regulated by NAADP, recent studies have challenged this. By generating the first mouse line with demonstrable absence of both Tpcn1 and Tpcn2 expression (Tpcn1/2−/−), we show that the loss of endogenous TPCs abolished NAADP-dependent ...
Vitreal delivery of AAV vectored Cnga3 restores cone function in CNGA3−/−/Nrl−/− mice, an all-cone model of CNGA3 achromatopsia
Human Molecular Genetics, Vol. 24, No.13, 3699–3707, doi: 10.1093/hmg/ddv114
The CNGA3−/−/Nrl−/− mouse is a cone-dominant model with Cnga3 channel deficiency, which partially mimics the all cone foveal structure of human achromatopsia 2 with CNGA3 mutations. Although subretinal (SR) AAV vector administration can transfect retinal cells efficiently, the injection-induced retinal detachment can cause retinal damage, particularly when SR ...
Bio Essays, online article
Traditionally, the impairment of cognitive functions in Alzheimeŕs disease (AD) is thought to result from a reduction in neuronal and synaptic activities, and ultimately cell death. Here, we review recent in vivo evidence from mouse models and human patients indicating that, particularly in early stages of AD, neuronal circuits are hyperactive instead of ...
Neuroscience’s answer to the Nobel Prize - The Brain Prize 2015 - goes in part to CIPSM researcher Arthur Konnerth for the invention, development and application of the revolutionary technique two-photon microscopy
The Brain Prize, Grete Lundbeck European Brain Research Foundation
Copenhagen, 9th March 2015: The world’s most valuable (€1m) neuroscience prize, The Brain Prize has been awarded, to CIPSM researcher Arthur Konnerth and three other scientists for the invention and development of two-photon microscopy, a transformative tool in brain research. Two-photon microscopy is one of a handful of techniques which over the last 15 years ...
ACS Chem. Neurosci., online article
Nicotinic acetylcholine receptors (nAChRs) are essential for cellular communication in higher organisms. Even though a vast pharmacological toolset to study cholinergic systems has been developed, control of endogenous neuronal nAChRs with high spatiotemporal precision has been lacking. To address this issue, we have generated photoswitchable nAChR agonists and ...
Science, online article
Ebola virus causes sporadic outbreaks of lethal hemorrhagic fever in humans, but there is no currently approved therapy. Cells take up Ebola virus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebola virus entry into host cells requires the endosomal ...
Chem. Commun., online article
Azobenzene photoresponsive elements can be installed on sulfonylureas, yielding optical control over pancreatic beta cell function and insulin release. An obstacle to such photopharmacological approaches remains the use of ultraviolet-blue illumination. Herein, we synthesize and test a novel yellow light-activated sulfonylurea based on a heterocyclic azobenzene ...
J. Chem. Theory Comput, online article
Polytwistane is an intriguing hydrocarbon nanorod that has not been experimentally realized to date. To facilitate its identification in complex reaction mixtures, the 1H and 13C nuclear magnetic resonance (NMR) spectra of idealized polytwistane were calculated using two distinct quantum chemical approaches. In addition, the NMR spectra of related hydrocarbon ...
Biological Chemistry, online article
Redox signals have emerged as important regulators of cellular physiology and pathology. The advent of redox imaging in vertebrate systems now provides the opportunity to dynamically visualize redox signaling during development and disease. In this review, we summarize recent advances in the generation of genetically encoded redox indicators (GERIs), introduce ...
European Journal of Pharmaceutics and Biopharmaceutics, Volume 95, Part B, Pages 343–352, doi:10.1016/j.ejpb.2015.01.009
European Journal of Pharmaceutics and Biopharmaceutics, online article
Adeno-associated virus (AAV) vectors are the most widely used vehicle systems for neuronal gene transfer. This popularity is based on the non-pathogenic nature of AAVs and their versatility making them a multifunctional vector system for basic research and clinical applications. AAVs are successfully applied in clinical and pre-clinical gene therapy studies for ...
Quick and reliable method for retina dissociation and separation of rod photoreceptor perikarya from adult mice
MethodsX, Volume 2, 2015, Pages 39–46, doi:10.1016/j.mex.2015.01.002
A pure and abundant population of adult rod perikarya can be exploited in different studies concerning nuclear functions such as gene expression analyses which aim at elucidating the relationship between cell type and disease. Sorting is based either on specific cell-surface markers or fluorescently labeled reporter proteins. Here, we describe a simple and ...
Cell, online article
Dendrites are the predominant entry site for excitatory synaptic potentials in most types of central neurons. There is increasing evidence that dendrites are not just passive transmitting devices but play active roles in synaptic integration through linear and non-linear mechanisms. Frequently, excitatory synapses are formed on dendritic spines. In addition to ...