ALBERT

Description: Publication date: Available online 20 August 2015 Source: Cell Reports Author(s): Bettina Schreiner, Elisa Romanelli, Pawel Liberski, Barbara Ingold-Heppner, Bettina Sobottka-Brillout, Tom Hartwig, Vijay Chandrasekar, Helge Johannssen, Hanns Ulrich Zeilhofer, Adriano Aguzzi, Frank Heppner, Martin Kerschensteiner, Burkhard Becher Although the importance of reactive astrocytes during CNS pathology is well established, the function of astroglia in adult CNS homeostasis is less well understood. With the use of conditional, astrocyte-restricted protein synthesis termination, we found that selective paralysis of GFAP + astrocytes in vivo led to rapid neuronal cell loss and severe motor deficits. This occurred while structural astroglial support still persisted and in the absence of any major microvascular damage. Whereas loss of astrocyte function did lead to microglial activation, this had no impact on the neuronal loss and clinical decline. Neuronal injury was caused by oxidative stress resulting from the reduced redox scavenging capability of dysfunctional astrocytes and could be prevented by the in vivo treatment with scavengers of reactive oxygen and nitrogen species (ROS/RNS). Our results suggest that the subpopulation of GFAP + astrocytes maintain neuronal health by controlling redox homeostasis in the adult CNS. Graphical abstract Teaser Schreiner et al. examine the functional contribution of astrocytes to tissue homeostasis in the adult CNS and identify the redox-scavenging capacity of GFAP + astrocytes as a key factor for neuronal health in vivo. The importance of the metabolic integrity of the glia-neuron interface highlights potential therapies for the treatment of neurodegenerative diseases.

Description: Publication date: Available online 20 August 2015 Source: Cell Reports Author(s): Priya Srikanth, Karam Han, Dana G. Callahan, Eugenia Makovkina, Christina R. Muratore, Matthew A. Lalli, Honglin Zhou, Justin D. Boyd, Kenneth S. Kosik, Dennis J. Selkoe, Tracy L. Young-Pearse Genetic and clinical association studies have identified disrupted in schizophrenia 1 ( DISC1 ) as a candidate risk gene for major mental illness. DISC1 is interrupted by a balanced chr(1;11) translocation in a Scottish family in which the translocation predisposes to psychiatric disorders. We investigate the consequences of DISC1 interruption in human neural cells using TALENs or CRISPR-Cas9 to target the DISC1 locus. We show that disruption of DISC1 near the site of the translocation results in decreased DISC1 protein levels because of nonsense-mediated decay of long splice variants. This results in an increased level of canonical Wnt signaling in neural progenitor cells and altered expression of fate markers such as Foxg1 and Tbr2. These gene expression changes are rescued by antagonizing Wnt signaling in a critical developmental window, supporting the hypothesis that DISC1-dependent suppression of basal Wnt signaling influences the distribution of cell types generated during cortical development. Graphical abstract Teaser Srikanth et al. report the generation of isogenic hiPSC lines with engineered mutations in two locations within the DISC1 gene. This disease-relevant disruption shows a loss of long isoforms, which, in turn, affects neural progenitor cell proliferation, baseline WNT signaling, and the expression of NPC fate markers such as FoxG1 and Tbr2.

Description: Publication date: Available online 20 August 2015 Source: Cell Reports Author(s): Ivana Vonkova, Antoine-Emmanuel Saliba, Samy Deghou, Kanchan Anand, Stefano Ceschia, Tobias Doerks, Augustinus Galih, Karl G. Kugler, Kenji Maeda, Vladimir Rybin, Vera van Noort, Jan Ellenberg, Peer Bork, Anne-Claude Gavin Many cellular processes involve the recruitment of proteins to specific membranes, which are decorated with distinctive lipids that act as docking sites. The phosphoinositides form signaling hubs, and we examine mechanisms underlying recruitment. We applied a physiological, quantitative, liposome microarray-based assay to measure the membrane-binding properties of 91 pleckstrin homology (PH) domains, the most common phosphoinositide-binding target. 10,514 experiments quantified the role of phosphoinositides in membrane recruitment. For most domains examined, the observed binding specificity implied cooperativity with additional signaling lipids. Analyses of PH domains with similar lipid-binding profiles identified a conserved motif, mutations in which—including some found in human cancers—induced discrete changes in binding affinities in vitro and protein mislocalization in vivo. The data set reveals cooperativity as a key mechanism for membrane recruitment and, by enabling the interpretation of disease-associated mutations, suggests avenues for the design of small molecules targeting PH domains. Graphical abstract Teaser Vonkova et al. systematically quantify the lipid-binding properties of 91 pleckstrin homology (PH) domains using a physiological, quantitative, liposome microarray-based assay. The data set reveals that cooperativity between lipids is a key mechanism for membrane recruitment of PH domains.

Description: Publication date: Available online 20 August 2015 Source: Cell Reports Author(s): Ju-Hyun Lee, Mary Kate McBrayer, Devin M. Wolfe, Luke J. Haslett, Asok Kumar, Yutaka Sato, Pearl P.Y. Lie, Panaiyur Mohan, Erin E. Coffey, Uday Kompella, Claire H. Mitchell, Emyr Lloyd-Evans, Ralph A. Nixon Presenilin 1 (PS1) deletion or Alzheimer’s disease (AD)-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation and instability of vATPase V0a1 subunit, causing deficient lysosomal vATPase assembly and function. We further demonstrate that elevated lysosomal pH in Presenilin 1 knockout (PS1KO) cells induces abnormal Ca 2+ efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca 2+ . In WT cells, blocking vATPase activity or knockdown of either PS1 or the V0a1 subunit of vATPase reproduces all of these abnormalities. Normalizing lysosomal pH in PS1KO cells using acidic nanoparticles restores normal lysosomal proteolysis, autophagy, and Ca 2+ homeostasis, but correcting lysosomal Ca 2+ deficits alone neither re-acidifies lysosomes nor reverses proteolytic and autophagic deficits. Our results indicate that vATPase deficiency in PS1 loss-of-function states causes lysosomal/autophagy deficits and contributes to abnormal cellular Ca 2+ homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism. Graphical abstract Teaser Lee et al. present evidence establishing that Presenilin 1 loss of function elevates lysosomal pH via loss of V0a1 vATPase subunits. Besides disrupting autophagy, elevated lysosomal pH hyperactivates the TRPML1 calcium channel, causing increased lysosomal calcium efflux and cytosolic calcium elevation, thus linking two AD-related presenilin phenotypes to vATPase deficiency.

Description: Publication date: Available online 20 August 2015 Source: Cell Reports Author(s): Soraia Barão, Annette Gärtner, Eduardo Leyva-Díaz, Galina Demyanenko, Sebastian Munck, Tine Vanhoutvin, Lujia Zhou, Melitta Schachner, Guillermina López-Bendito, Patricia F. Maness, Bart De Strooper ΒACE1 is the major drug target for Alzheimer’s disease, but we know surprisingly little about its normal function in the CNS. Here, we show that this protease is critically involved in semaphorin 3A (Sema3A)-mediated axonal guidance processes in thalamic and hippocampal neurons. An active membrane-bound proteolytic CHL1 fragment is generated by BACE1 upon Sema3A binding. This fragment relays the Sema3A signal via ezrin-radixin-moesin (ERM) proteins to the neuronal cytoskeleton. APH1B-γ-secretase-mediated degradation of this fragment stops the Sema3A-induced collapse and sensitizes the growth cone for the next axonal guidance cue. Thus, we reveal a cycle of proteolytic activity underlying growth cone collapse and restoration used by axons to find their correct trajectory in the brain. Our data also suggest that BACE1 and γ-secretase inhibition have physiologically opposite effects in this process, supporting the idea that combination therapy might attenuate some of the side effects associated with these drugs. Graphical abstract Teaser Barão et al. show that the Alzheimer’s-disease-related proteases, BACE1 and APH1B-γ-secretase, control axonal guidance by regulating growth cone dynamics. BACE1 cleaves CHL1, inducing growth cone collapse. Subsequently, γ-secretase activity stops the collapse and axonal growth resumes. Therefore, testing of inhibitors of these proteases in humans should proceed with caution.

Description: Publication date: Available online 20 August 2015 Source: Cell Reports Author(s): Alexander Harms, Frédéric Valentin Stanger, Patrick Daniel Scheu, Imke Greet de Jong, Arnaud Goepfert, Timo Glatter, Kenn Gerdes, Tilman Schirmer, Christoph Dehio Toxin-antitoxin (TA) modules are ubiquitous molecular switches controlling bacterial growth via the release of toxins that inhibit cell proliferation. Most of these toxins interfere with protein translation, but a growing variety of other mechanisms hints at a diversity that is not yet fully appreciated. Here, we characterize a group of FIC domain proteins as toxins of the conserved and abundant FicTA family of TA modules, and we reveal that they act by suspending control of cellular DNA topology. We show that FicTs are enzymes that adenylylate DNA gyrase and topoisomerase IV, the essential bacterial type IIA topoisomerases, at their ATP-binding site. This modification inactivates both targets by blocking their ATPase activity, and, consequently, causes reversible growth arrest due to the knotting, catenation, and relaxation of cellular DNA. Our results give insight into the regulation of DNA topology and highlight the remarkable plasticity of FIC domain proteins. Graphical abstract Teaser Harms et al. reveal that the FicTA toxin-antitoxin module acts via adenylylation of DNA gyrase and topoisomerase IV. This modification inactivates both targets by blocking the ATPase activity that is central to their enzymatic functions, and it reversibly inhibits bacterial growth via the knotting, catenation, and relaxation of cellular DNA.

Description: Publication date: Available online 20 August 2015 Source: Cell Reports Author(s): Takaharu Kanno, Davide G. Berta, Camilla Sjögren The structural maintenance of chromosome (SMC) protein complexes cohesin and condensin and the Smc5/6 complex (Smc5/6) are crucial for chromosome dynamics and stability. All contain essential ATPase domains, and cohesin and condensin interact with chromosomes through topological entrapment of DNA. However, how Smc5/6 binds DNA and chromosomes has remained largely unknown. Here, we show that purified Smc5/6 binds DNA through a mechanism that requires ATP hydrolysis by the complex and circular DNA to be established. This also promotes topoisomerase 2-dependent catenation of plasmids, suggesting that Smc5/6 interconnects two DNA molecules using ATP-regulated topological entrapment of DNA, similar to cohesin. We also show that a complex containing an Smc6 mutant that is defective in ATP binding fails to interact with DNA and chromosomes and leads to cell death with concomitant accumulation of DNA damage when overexpressed. Taken together, these results indicate that Smc5/6 executes its cellular functions through ATP-regulated intermolecular DNA linking. Graphical abstract Teaser Kanno et al. have found that Smc5/6 interacts with DNA by two different mechanisms. One is based on electrostatic interactions that require ATP binding to Smc6. The other leads to topological entrapment and demands ATP hydrolysis by the complex. The results show that Smc5/6 is an ATP-dependent intermolecular DNA linker.

Description: Publication date: 18 August 2015 Source: Cell Reports, Volume 12, Issue 7 Author(s): Marvin L. Meistrich, Gunapala Shetty In this issue of Cell Reports , DeFalco et al. (2015) characterize a novel macrophage population associated with the peritubular lamina of mouse testes. These macrophages may create a niche not for the self-renewal of stem cells but rather the induction of their differentiation.

Description: Publication date: Available online 13 August 2015 Source: Cell Reports Author(s): Kavita R. Sharma, Brittany L. Enzmann, Yvonne Schmidt, Dani Moore, Graeme R. Jones, Jane Parker, Shelley L. Berger, Danny Reinberg, Laurence J. Zwiebel, Bernhard Breit, Jürgen Liebig, Anandasankar Ray The sophisticated organization of eusocial insect societies is largely based on the regulation of complex behaviors by hydrocarbon pheromones present on the cuticle. We used electrophysiology to investigate the detection of cuticular hydrocarbons (CHCs) by female-specific olfactory sensilla basiconica on the antenna of Camponotus floridanus ants through the utilization of one of the largest family of odorant receptors characterized so far in insects. These sensilla, each of which contains multiple olfactory receptor neurons, are differentially sensitive to CHCs and allow them to be classified into three broad groups that collectively detect every hydrocarbon tested, including queen and worker-enriched CHCs. This broad-spectrum sensitivity is conserved in a related species, Camponotus laevigatus , allowing these ants to detect CHCs from both nestmates and non-nestmates. Behavioral assays demonstrate that these ants are excellent at discriminating CHCs detected by the antenna, including enantiomers of a candidate queen pheromone that regulates the reproductive division of labor. Graphical abstract Teaser Sharma et al. show that ants can detect a number of hydrocarbons present on the cuticle, therefore recognizing different castes such as workers and queens from their own colony as well as different colonies. They also show that ants are able to smell and discriminate minor differences among hydrocarbons.

Description: Publication date: Available online 13 August 2015 Source: Cell Reports Author(s): Sanjeev Kumar, Jing Liu, Paul Pang, A. Michaela Krautzberger, Antoine Reginensi, Haruhiko Akiyama, Andreas Schedl, Benjamin D. Humphreys, Andrew P. McMahon After acute kidney injury (AKI), surviving cells within the nephron proliferate and repair. We identify Sox9 as an acute epithelial stress response in renal regeneration. Translational profiling after AKI revealed a rapid upregulation of Sox9 within proximal tubule (PT) cells, the nephron cell type most vulnerable to AKI. Descendants of Sox9 + cells generate the bulk of the nephron during development and regenerate functional PT epithelium after AKI-induced reactivation of Sox9 after renal injury. After restoration of renal function post-AKI, persistent Sox9 expression highlights regions of unresolved damage within injured nephrons. Inactivation of Sox9 in PT cells pre-injury indicates that Sox9 is required for the normal course of post-AKI recovery. These findings link Sox9 to cell intrinsic mechanisms regulating development and repair of the mammalian nephron. Graphical abstract Teaser Surviving tubular epithelial cells repair the nephron after acute kidney injury (AKI). Kumar et al. identify Sox9 activation as a rapid response to AKI within repairing cells of the damaged proximal tubule segment. Sox9 activation is required for a normal repair process.