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Advances in Neurobiology 29 Cara-Lynne Schengrund Robert K. Yu Editors Glycobiology of the Nervous System Second Edition Advances in Neurobiology Volume 29 Series Editor Arne Schousboe, Department of Drug Design & Pharmacology University of Copenhagen Copenhagen, Denmark Advances in Neurobiology covers basic research in neurobiology and neuro chemistry. It provides indepth, booklength treatment of some of the most important topics in neuroscience including molecular and pharmacological aspects. The main audiences of the series are basic science researchers and graduate students as well as clinicians including neuroscientists (neurobiologists and neurochemists) and neurologists. Advances in Neurobiology is indexed in PubMed, Google Scholar, and the Thompson Reuters Book Citation Index. Editor-In-Chief Arne Schousboe University of Copenhagen Editorial Board Members Marta Antonelli, University of Buenos Aires, Argentina Michael Aschner, Albert Einstein College of Medicine, New York Philip Beart, University of Melbourne, Australia Stanislaw Jerzy Czuczwar, Medical University of Lublin, Poland Ralf Dringen, University of Bremen, Germany Mary C. McKenna, University of Maryland, Baltimore Arturo Ortega, National Polytechnic Institute, Mexico City, Mexico Vladimir Parpura, University of Alabama, Birmingham Caroline Rae, Neuroscience Research Australia, Sydney Ursula Sonnewald, Norwegian University of Science and Technology, Trondheim Alexei Verkhratsky, University of Manchester, UK H. Steve White, University of Washington, Seattle Albert Yu, Peking University, China David Aidong Yuan, Nathan S. Klein Institute for Psychiatric Research, Orangeburg CaraLynne Schengrund • Robert K. Yu Editors Glycobiology of the Nervous System Second Edition Editors CaraLynne Schengrund, PhD Robert K. Yu, PhD Biochemistry and Molecular Biology Department of Neuroscience The Pennsylvania State University and Regenerative Medicine Hershey, PA, USA Medical College of Georgia Augusta University Augusta, GA, USA ISSN 21905215 ISSN 21905223 (electronic) Advances in Neurobiology ISBN 9783031123894 ISBN 9783031123900 (eBook) https://doi.org/10.1007/9783031123900 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG, 2014, 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Preface According to PubMed, between 2013, when much of the work that appeared in the first edition of this book was done, and the start of 2022, over 4200 manuscripts were published that dealt with carbohydrates and neural function, with about 28% of them appearing during the SARSCoV2 pandemic years of 2019–2022 (March). Of the approximately 490,000 publications listed by PubMed on carbohydrates per se between 2013 and 2022, about 36% appeared between 2019 and 2022 (March). The numbers just emphasize the growing interest in glycobiology and the prescience of the 2012 publication of the National Academy of Science–sponsored committee report that discussed the importance of glycomics and glycosciences and was titled “Transforming glycoscience, a roadmap for the future” (The National Academies Press 2012). It is the growing interest in the potential roles of carbohydrates in neu ral function that presumably accounts for the interest the first edition of this book generated and which led Springer to request an update. While the initial chapters have been updated or provided from a fresh perspec tive, they are included for people relatively new to the field of neural cell anatomy and/or carbohydrate chemistry/biochemistry as they provide an introduction to cells that comprise the nervous system and a basic understanding of the complexity of oligosaccharide synthesis. Glycoconjugates are formed by the addition of one sugar to another on either a lipid or protein as described in Chap. 1. Recent evidence indi cates that small, noncoding RNAs can also be glycosylated via Nglycan biosynthe sis and are primarily associated with cell membranes (https://doi.org/10.1016/j. cell.2021.04.023). Future reports are needed to provide more information about their potential roles in cells. The lack of a defined template for oligosaccharide synthesis such as there is for protein synthesis means that there can be significant variability in the structures formed, and it is well known that errors in glycosylation can lead to significant dis ruptions in neural function. An introduction to cells found in the central nervous system (CNS) and how all of the cells function together to accomplish perception, integration, memory, and the generation of behaviors are provided in Chap. 2. Interruption of those interactions results in various disruptions of normal neural function. Chapters 3, 4, and 5 discuss Nlinked glycoproteins, Olinked v vi Preface glycoconjugates, and glycosaminoglycans, respectively. Each reviews methods of synthesis of glycan moieties and includes examples of their roles in diseases affect ing the nervous system. It is also apparent that the number of possible products formed upon linking two or more sugars together is much greater than that formed when a similar number of amino acids form a polypeptide, a fact that makes their structural analysis more difficult. A discussion about the structural analysis of oligosaccharides and glycoconju gates using NMR is provided in Chap. 6, and updated information about utilization of mass spectrometry in glycomics is available at https://doi.org/10.1042/ BST20190861. As pointed out in discussion of glycoconjugates and their roles in axon growth/guidance as well as voltagegated channels in Chap. 7, it is only because of recent technological advances in biophysicochemical and imaging anal yses that researchers have been able to define the structures of glycoconjugates and changes that either cause or occur during disease. Subsequent chapters become more focused, pointing out specific errors in pro teins responsible for specific steps in glycosylation/deglycosylation and how they can affect individuals in whom they are expressed. The sheer number of these errors can be seen in the discussion of congenital disorders of glycosylation presented in Chap. 8, while Chap. 9 focuses on brain OGlcNacylation, discussing molecular mechanisms and clinical phenotypes affected if it goes awry. Chapters 10, 11, 12, and 13 focus on the remarkable progress made in identifying the role(s) of ganglio sides in neural function, starting with their roles in determining the fate of neuronal precursor cells (Chap. 10). This is followed by a discussion in Chap. 11 of how the structure of cell surface gangliosides, whose intracellular synthesis is completed in the Golgi, can be modified by plasma membrane–associated glycohydrolases. The authors discuss how these changes can affect membrane microdomain curvature which in turn can modify behavior of proteins in that area. Chapter 12 presents details about inborn errors of metabolism affecting neuronal gangliosides and gly cosphingolipids and their attendant pathologies, while Chap. 13 focuses on findings of ganglioside changes/interactions associated with neurodegenerative disorders such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. Chapter 14 reviews glycosphingolipid deficiencies and broadens the concept of taking advantage of our growing knowledge of their ability to affect behavior of a variety of molecules by using glycosphingolipid replacement therapy to ameliorate deficiencies affecting the CNS. Errors in carbohydrate metabolism aren’t the only ways by which carbohydrates can affect the central nervous system. The role of carbohydrates in the action of pathogens that affect the CNS is discussed in Chap. 15, which points out that oligo saccharides on the target cell can function as receptors for carbohydratebinding proteins on the pathogen or carbohydrates on the pathogen may be bound by carbohydrate binding proteins on the target cell. As these molecules become identi fied, methods are being developed to block such interactions using specific antibod ies, inhibitors of carbohydrate binding, or molecules to block release of nascent virus from the cells. A potential problem can occur when an infection that stimu lates an immune response results in production of antibodies that recognize not just Preface vii carbohydrates on the pathogen but molecules on human cells as well. Referred to as “molecular mimicry,” this potential problem is discussed in Chap. 16. As stated at the start, progress in the study of glycoconjugates and their roles in the CNS has benefited from the development of (1) animal models, (2) methods for carbohydrate characterization, and (3) imaging. As details accrue regarding the molecular effects of specific changes caused by defective expression of specific glycoconjugates, it is anticipated that those findings will lead to development of therapies able to ameliorate the attendant pathologies. Finally, we want to thank the authors that either updated or provided us with new chapters for this volume. Some of them dealt with disruptions caused by SARS CoV 2, while others dealt not only with the pandemic but also politically induced problems, and in some cases serious health conditions. To all, our sincere thank you for all your work. To readers, we hope that you find chapters that interest you, and if you are just starting to do research in this area, we hope you discover an unan swered question that stimulates you to try to find the answer. Hershey, PA, USA CaraLynne Schengrund Augusta, GA, USA Robert K. Yu Postscript: In Memoriam It was with sadness that I learned that my coeditor, Dr. Robert K. Yu, lost his on going battle with Parkinson’s disease on May 18, 2022. Without him, this book, in either the first edition or this one, would not exist. It was Bob, whom I have known for over 50 years as both a colleague and good friend, who asked me to be his co chair for a symposium on “glycobiology of the ner vous system” that he was proposing for the 2012 meet ing of the American Society for Neurochemistry. Springer noticed it and thought it a timely topic for a book. We agreed. The book was written, wellreceived, and an update requested. Despite knowing that he had Parkinson’s, Bob agreed that we should do it and indicated that he would write two chapters. Notwithstanding his declining health, Bob, in conjunction with his coau thors, completed them and sent them to me. I knew Bob was relieved when they were finished as he told me he had met his obligations. It was just a short time later that he was hospitalized, but even then, he kept in touch and was happy when I told him all chapters had been sent to Springer. I relate this to indicate the dedication Bob had to his research, to his excitement when his hypotheses were confirmed by experimentation, and to his following through on commitments that he made. Personally, I will miss his friendship, enthusiasm about his work, and enjoyment of life and his family. For those interested in learning about Bob’s scientific life, honors, and publica tions, see https://doi.org/10.1007/s11064 011 0445y . ix Contents 1 Introduction to the Complexity of Cell Surface and Tissue Matrix Glycoconjugates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Veer P. Bhavanandan and D. Channe Gowda 2 Cells of the Central Nervous System: An Overview of Their Structure and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 John W. Bigbee 3 Synthesis, Processing, and Function of N-Glycans in N-Glycoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Erhard Bieberich 4 Synthesis of O-Linked Glycoconjugates in the Nervous System . . . . 95 JinIchi Inokuchi, Shinji Go, and Yoshio Hirabayashi 5 Chemistry and Function of Glycosaminoglycans in the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Nancy B. Schwartz and Miriam S. Domowicz 6 Structural Analysis of Oligosaccharides and Glycoconjugates Using NMR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 Yoshiki Yamaguchi, Takumi Yamaguchi, and Koichi Kato 7 Glycans and Carbohydrate-Binding/Transforming Proteins in Axon Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 José AbadRodríguez, María Elvira Brocca, and Alonso Miguel Higuero 8 Neurological Consequences of Congenital Disorders of Glycosylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Justyna Paprocka 9 Brain O-GlcNAcylation: From Molecular Mechanisms to Clinical Phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 Batuhan Uygar and Olof Lagerlöf xi