Drosophila Mitochondrial Proteome Is Partially Corrected with Exercise
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Electrical Synapses Are Drivers of Neural Plasticity Through Passage of Small Molecules
Electrical Synapses are Drivers of Neural Plasticity Through Passage of Small Molecules Lisa Voelker A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2019 Reading Committee: Jihong Bai, Chair Linda Buck Cecilia Moens Program Authorized to Offer Degree: Molecular and Cellular Biology ©Copyright 2019 Lisa Voelker 2 University of Washington Abstract Electrical Synapses are Drivers of Neural Plasticity through Passage of Small Molecules Lisa Voelker Chair of the Supervisory Committee: Jihong Bai Department of Biochemistry In order to respond to changing environments and fluctuations in internal states, animals adjust their behavior through diverse neuromodulatory mechanisms. In this study we show that electrical synapses between the ASH primary quinine-detecting sensory neurons and the neighboring ASK neurons are required for modulating the aversive response to the bitter tastant quinine in C. elegans. Mutant worms that lack the electrical synapse proteins INX-18 and INX-19 become hypersensitive to dilute quinine. Cell-specific rescue experiments indicate that inx-18 operates in ASK while inx-19 is required in both ASK and ASH for proper quinine sensitivity. Imaging analyses find that INX-19 in ASK and ASH localizes to the same regions in the nerve ring, suggesting that both sides of ASK-ASH electrical synapses contain INX-19. While inx-18 and inx-19 mutant animals have a similar behavioral phenotype, several lines of evidence suggest the proteins encoded by these genes play different roles in modulating the aversive quinine response. First, INX-18 and INX-19 localize 3 to different regions of the nerve ring, indicating that they are not present in the same synapses. -
New Group of Transmembrane Proteins Associated with Desiccation Tolerance in the Anhydrobiotic Midge Polypedilum Vanderplanki Taisiya A
www.nature.com/scientificreports OPEN New group of transmembrane proteins associated with desiccation tolerance in the anhydrobiotic midge Polypedilum vanderplanki Taisiya A. Voronina1,6, Alexander A. Nesmelov1,6, Sabina A. Kondratyeva1, Ruslan M. Deviatiiarov1, Yugo Miyata2, Shoko Tokumoto3, Richard Cornette2, Oleg A. Gusev1,4,5, Takahiro Kikawada2,3* & Elena I. Shagimardanova1* Larvae of the sleeping chironomid Polypedilum vanderplanki are known for their extraordinary ability to survive complete desiccation in an ametabolic state called “anhydrobiosis”. The unique feature of P. vanderplanki genome is the presence of expanded gene clusters associated with anhydrobiosis. While several such clusters represent orthologues of known genes, there is a distinct set of genes unique for P. vanderplanki. These include Lea-Island-Located (LIL) genes with no known orthologues except two of LEA genes of P. vanderplanki, PvLea1 and PvLea3. However, PvLIL proteins lack typical features of LEA such as the state of intrinsic disorder, hydrophilicity and characteristic LEA_4 motif. They possess four to fve transmembrane domains each and we confrmed membrane targeting for three PvLILs. Conserved amino acids in PvLIL are located in transmembrane domains or nearby. PvLEA1 and PvLEA3 proteins are chimeras combining LEA-like parts and transmembrane domains, shared with PvLIL proteins. We have found that PvLil genes are highly upregulated during anhydrobiosis induction both in larvae of P. vanderplanki and P. vanderplanki-derived cultured cell line, Pv11. Thus, PvLil are a new intriguing group of genes that are likely to be associated with anhydrobiosis due to their common origin with some LEA genes and their induction during anhydrobiosis. Anhydrobiosis is the ability of an organism to survive complete desiccation in the ametabolic state. -
Functions of Nogo Proteins and Their Receptors in the Nervous System
REVIEWS Functions of Nogo proteins and their receptors in the nervous system Martin E. Schwab Abstract | The membrane protein Nogo-A was initially characterized as a CNS-specific inhibitor of axonal regeneration. Recent studies have uncovered regulatory roles of Nogo proteins and their receptors — in precursor migration, neurite growth and branching in the developing nervous system — as well as a growth-restricting function during CNS maturation. The function of Nogo in the adult CNS is now understood to be that of a negative regulator of neuronal growth, leading to stabilization of the CNS wiring at the expense of extensive plastic rearrangements and regeneration after injury. In addition, Nogo proteins interact with various intracellular components and may have roles in the regulation of endoplasmic reticulum (ER) structure, processing of amyloid precursor protein and cell survival. Nogo proteins were discovered, and have been exten- The amino-terminal segments of the proteins sively studied, in the context of injury and repair of fibre encoded by the different RTN genes have differing tracts in the CNS1 — a topic of great research interest lengths and there is no homology between them3,5. The and clinical relevance. However, much less in known N termini of the RTN4 products Nogo-A and Nogo-B are about the physiological functions of Nogo proteins in identical, consisting of a 172-amino acid sequence that development and in the intact adult organism, including is encoded by a single exon (exon 1) that is followed by in the brain. Through a number of recent publications, a short exon 2 and, in Nogo-A, by the very long exon Nogo proteins have emerged as important regulators of 3 encoding 800 amino acids2,6 (FIG. -
Characterization of Innexin Gene Expression and Functional Roles of Gap-Junctional Communication in Planarian Regeneration
Developmental Biology 287 (2005) 314 – 335 www.elsevier.com/locate/ydbio Characterization of innexin gene expression and functional roles of gap-junctional communication in planarian regeneration Taisaku Nogi, Michael Levin * Department of Cytokine Biology, The Forsyth Institute, 140 The Fenway, Boston, MA 02115, USA Department of Oral and Developmental Biology, Harvard School of Dental Medicine, 140 The Fenway, Boston, MA 02115, USA Received for publication 17 January 2005, revised 20 August 2005, accepted 1 September 2005 Available online 21 October 2005 Abstract Planaria possess remarkable powers of regeneration. After bisection, one blastema regenerates a head, while the other forms a tail. The ability of previously-adjacent cells to adopt radically different fates could be due to long-range signaling allowing determination of position relative to, and the identity of, remaining tissue. However, this process is not understood at the molecular level. Following the hypothesis that gap-junctional communication (GJC) may underlie this signaling, we cloned and characterized the expression of the Innexin gene family during planarian regeneration. Planarian innexins fall into 3 groups according to both sequence and expression. The concordance between expression-based and phylogenetic grouping suggests diversification of 3 ancestral innexin genes into the large family of planarian innexins. Innexin expression was detected throughout the animal, as well as specifically in regeneration blastemas, consistent with a role in long-range signaling relevant to specification of blastema positional identity. Exposure to a GJC-blocking reagent which does not distinguish among gap junctions composed of different Innexin proteins (is not subject to compensation or redundancy) often resulted in bipolar (2-headed) animals. -
Stem Cells and Ion Channels
Stem Cells International Stem Cells and Ion Channels Guest Editors: Stefan Liebau, Alexander Kleger, Michael Levin, and Shan Ping Yu Stem Cells and Ion Channels Stem Cells International Stem Cells and Ion Channels Guest Editors: Stefan Liebau, Alexander Kleger, Michael Levin, and Shan Ping Yu Copyright © 2013 Hindawi Publishing Corporation. All rights reserved. This is a special issue published in “Stem Cells International.” All articles are open access articles distributed under the Creative Com- mons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board Nadire N. Ali, UK Joseph Itskovitz-Eldor, Israel Pranela Rameshwar, USA Anthony Atala, USA Pavla Jendelova, Czech Republic Hannele T. Ruohola-Baker, USA Nissim Benvenisty, Israel Arne Jensen, Germany D. S. Sakaguchi, USA Kenneth Boheler, USA Sue Kimber, UK Paul R. Sanberg, USA Dominique Bonnet, UK Mark D. Kirk, USA Paul T. Sharpe, UK B. Bunnell, USA Gary E. Lyons, USA Ashok Shetty, USA Kevin D. Bunting, USA Athanasios Mantalaris, UK Igor Slukvin, USA Richard K. Burt, USA Pilar Martin-Duque, Spain Ann Steele, USA Gerald A. Colvin, USA EvaMezey,USA Alexander Storch, Germany Stephen Dalton, USA Karim Nayernia, UK Marc Turner, UK Leonard M. Eisenberg, USA K. Sue O’Shea, USA Su-Chun Zhang, USA Marina Emborg, USA J. Parent, USA Weian Zhao, USA Josef Fulka, Czech Republic Bruno Peault, USA Joel C. Glover, Norway Stefan Przyborski, UK Contents Stem Cells and Ion Channels, Stefan Liebau, -
Ion Channels
UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. -
Hereditary Spastic Paraplegia: from Genes, Cells and Networks to Novel Pathways for Drug Discovery
brain sciences Review Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery Alan Mackay-Sim Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia; a.mackay-sim@griffith.edu.au Abstract: Hereditary spastic paraplegia (HSP) is a diverse group of Mendelian genetic disorders affect- ing the upper motor neurons, specifically degeneration of their distal axons in the corticospinal tract. Currently, there are 80 genes or genomic loci (genomic regions for which the causative gene has not been identified) associated with HSP diagnosis. HSP is therefore genetically very heterogeneous. Finding treatments for the HSPs is a daunting task: a rare disease made rarer by so many causative genes and many potential mutations in those genes in individual patients. Personalized medicine through genetic correction may be possible, but impractical as a generalized treatment strategy. The ideal treatments would be small molecules that are effective for people with different causative mutations. This requires identification of disease-associated cell dysfunctions shared across geno- types despite the large number of HSP genes that suggest a wide diversity of molecular and cellular mechanisms. This review highlights the shared dysfunctional phenotypes in patient-derived cells from patients with different causative mutations and uses bioinformatic analyses of the HSP genes to identify novel cell functions as potential targets for future drug treatments for multiple genotypes. Keywords: neurodegeneration; motor neuron disease; spastic paraplegia; endoplasmic reticulum; Citation: Mackay-Sim, A. Hereditary protein-protein interaction network Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery. Brain Sci. 2021, 11, 403. -
Innexin Specificity in Neural Development
Research Article 3379 Gap junction proteins are not interchangeable in development of neural function in the Drosophila visual system Kathryn D. Curtin*, Zhan Zhang and Robert J. Wyman Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA *Author for correspondence (e-mail: [email protected]) Accepted 12 June 2002 Journal of Cell Science 115, 3379-3388 (2002) © The Company of Biologists Ltd Summary Gap junctions (GJs) are composed of proteins from two Specifically, we tested several innexins for their ability to distinct families. In vertebrates, GJs are composed of rescue shakB2 and ogre mutant ERGs and found that, by connexins; a connexin hexamer on one cell lines up with and large, innexins are not interchangeable. We mapped a hexamer on an apposing cell to form the intercellular the protein regions required for this specificity by making channel. In invertebrates, GJs are composed of an molecular chimeras between shakB(N) and ogre and unrelated protein family, the innexins. Different testing their ability to rescue both mutants. Each chimera connexins have distinct properties that make them largely rescued either shakB or ogre but never both. Sequences in non-interchangeable in the animal. Innexins are also a the first half of each protein are necessary for functional large family with high sequence homology, and some specificity. Potentially crucial residues include a small functional differences have been reported. The biological number in the intracellular loop as well as a short stretch implication of innexin differences, such as their ability to just N-terminal to the second transmembrane domain. substitute for one another in the animal, has not been Temporary GJs, possibly between the retina and lamina, explored. -
Roles of Reticulons and Reeps in Organisation of Axonal Endoplasmic Reticlum in Drosophila
Roles of reticulons and REEPs in organisation of axonal endoplasmic reticlum in Drosophila Belgin Yalçın1, Niamh C. O’Sullivan1, Martin Stofanko1, Zi Han Kang, Annika Hartwich, Matt Thomas, Cahir J. O’Kane2 (1equal contributions; 2corresponding author) Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK The length of motor axons requires significant engineering for their formation and maintenance. Failures of this maintenance are seen in the Hereditary Spastic Paraplegias (HSPs), characterised by lower limb weakness, and degeneration of longer upper motor axons. To date over 50 causative Spastic Paraplegia Genes (SPGs) have been identified. Several encode endoplasmic reticulum membrane proteins, with intramembrane hairpin structures that curve and model ER membrane. Two of these protein families, reticulons and REEPs, are together required for formation of most tubular ER in yeast. To test whether they are also required for formation or maintenance of axonal ER, we have developed suitable markers in Drosophila, and analyzed mutants that lack members of these protein families. Drosophila has two reticulon genes, one of which, Rtnl1, is widely expressed. YFP-tagged Rtnl1 localises strongly in axons and presynaptic terminals, in contrast to most conventional ER markers. Rtnl1 knockdown reduces levels of smooth ER marker in longer distal motor axons, but not in shorter or proximal ones – analogous to HSP. This effect is also seen in labeled single axons, with no loss of ER continuity. Drosophila has six REEP genes, two of which are widely and highly expressed. ReepA is orthologous to mammalian REEPs 1 to 4, and ReepB to mammalian REEP5 and REEP6. We can detect ReepB::GFP but not ReepA::GFP in axons and presynaptic terminals. -
The Drosophila Innexin Multiprotein Family of Gap Junction Proteins
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Chemistry & Biology, Vol. 12, 515–526, May, 2005, ©2005 Elsevier Ltd All rights reserved. DOI 10.1016/j.chembiol.2005.02.013 Intercellular Communication: Review the Drosophila Innexin Multiprotein Family of Gap Junction Proteins Reinhard Bauer, Birgit Löer, Katinka Ostrowski, with the morphological description of gap junctions as Julia Martini, Andy Weimbs, Hildegard Lechner, having a “nexus” structure. Connexins comprise a and Michael Hoch* multigene family of integral membrane proteins, with 20 Institute of Molecular Physiology and Connexin isoforms identified in mice and 21 in humans Developmental Biology [9]. These proteins are characterized by two extracellu- University of Bonn lar domains, four membrane-spanning domains, and Poppelsdorfer Schloss three cytoplasmic domains, consisting of an intracellu- 53115 Bonn lar loop, and amino- and carboxy termini. Six Connexin Germany transmembrane protein units form a hemichannel, which is termed the Connexon (see [10] for review). In mam- mals, two hemichannels form a gap junction channel, Summary with each hemichannel provided by one of the two neighboring cells. These two hemichannels dock head- Gap junctions belong to the most conserved cellular to-head in the extracellular space to form a tightly structures in multicellular organisms, from Hydra to sealed, double-membrane intercellular gap junction man. They contain tightly packed clusters of hydro- channel. Gap junctions allow diffusional exchange of philic membrane channels connecting the cytoplasms ions, such as Ca2+, and metabolites, such as inositol of adjacent cells, thus allowing direct communication phosphates and cyclic nucleotides (see [11] and [12] of cells and tissues through the diffusion of ions, me- for review). -
A Single Legionella Effector Catalyzes a Multistep Ubiquitination Pathway to Rearrange Tubular Endoplasmic Reticulum for Replication
Article A Single Legionella Effector Catalyzes a Multistep Ubiquitination Pathway to Rearrange Tubular Endoplasmic Reticulum for Replication Graphical Abstract Authors Kristin M. Kotewicz, Vinay Ramabhadran, Nicole Sjoblom, ..., Jessica Behringer, Rebecca A. Scheck, Ralph R. Isberg Correspondence [email protected] In Brief Intracellular pathogens, including Legionella, target host organelles for replication. Kotewicz et al. show that Legionella generates an ER- encompassed replication compartment via Sde protein-mediated ubiquitination of host reticulon 4. Ubiquitination is mediated by sequential action of the ADP-ribosyltransferase and nucleotidase activities of Sde and independent of the host ubiquitination system. Highlights d Legionella Sde proteins remodel tubular ER to initiate intracellular replication d The tubular ER protein reticulon 4 is targeted by Sde proteins d ER remodeling requires ubiquitin transfer by Sde proteins d Ubiquitin transfer involves ADP-ribosyltransferase and nucleotidase activities Kotewicz et al., 2017, Cell Host & Microbe 21, 169–181 February 8, 2017 ª 2016 Elsevier Inc. http://dx.doi.org/10.1016/j.chom.2016.12.007 Cell Host & Microbe Article ASingleLegionella Effector Catalyzes a Multistep Ubiquitination Pathway to Rearrange Tubular Endoplasmic Reticulum for Replication Kristin M. Kotewicz,1,6 Vinay Ramabhadran,1,3,6 Nicole Sjoblom,2 Joseph P. Vogel,4 Eva Haenssler,1,7 Mengyun Zhang,1 Jessica Behringer,5 Rebecca A. Scheck,2 and Ralph R. Isberg1,3,8,* 1Department of Molecular Biology and Microbiology, Tufts University School of Medicine, 150 Harrison Ave., Boston, MA 02111, USA 2Department of Chemistry, Tufts University, 62 Talbot Ave., Medford, MA 02155, USA 3Howard Hughes Medical Institute, Tufts University School of Medicine, 150 Harrison Ave., Boston, MA 02111, USA 4Department of Molecular Microbiology, Washington University School of Medicine, St. -
A Conserved Amphipathic Helix Is Required for Membrane Tubule Formation by Yop1p
A conserved amphipathic helix is required for PNAS PLUS membrane tubule formation by Yop1p Jacob P. Brady, Jolyon K. Claridge, Peter G. Smith, and Jason R. Schnell1 Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom Edited by William F. DeGrado, School of Pharmacy, University of California, San Francisco, CA, and approved December 31, 2014 (received for review August 18, 2014) The integral membrane proteins of the DP1 (deleted in polyposis) C-terminal tubulin binding domains providing a link between ER and reticulon families are responsible for maintaining the high morphology and the cytoskeleton (19). membrane curvature required for both smooth endoplasmic retic- The RHDs are proposed to form hydrophobic hairpins too ulum (ER) tubules and the edges of ER sheets, and mutations in short to traverse the membrane fully, leading to greater dis- these proteins lead to motor neuron diseases, such as hereditary placement of lipids from the outer leaflet than from the in- spastic paraplegia. Reticulon/DP1 proteins contain reticulon ho- ner leaflet. By this mechanism, a combination of hydrophobic mology domains (RHDs) that have unusually long hydrophobic wedging and oligomeric scaffolding could lead to the stabiliza- segments and are proposed to adopt intramembrane helical hair- tion of the tubular ER membrane. However, there is currently pins that stabilize membrane curvature. We have characterized no structural information available for these intramembrane the secondary structure and dynamics of the DP1 family protein domains, and the exact mechanism of curvature generation and produced from the YOP1 gene (Yop1p) and identified a C-termi- stabilization remains unknown. The mechanism for exclusive nal conserved amphipathic helix (APH) that, on its own, interacts localization of RHD proteins to highly curved membranes also strongly with negatively charged membranes and is necessary remains unclear; however, the transmembrane domains have for membrane tubule formation.