Glycobiology of the Nervous System

Preface
Postscript: In Memoriam
Contents
Chapter 1: Introduction to the Complexity of Cell Surface and Tissue Matrix Glycoconjugates
1 Introduction
2 Monosaccharides: Building Blocks of Glycans
3 Formation of Oligosaccharides
4 Classification of Glycans
5 Structural Features of N-Glycans
6 Structural Features of O-Glycans
7 Biosynthesis of N- and O-Glycans
8 Glycosphingolipids
9 Structural Features of the Glycan Moieties of Glycosphingolipids
10 Synthesis and Functions of the Glycan Moieties of Glycolipids
11 Glycosylphosphatidylinositol Anchors: A Special Group of Glycolipids
12 Glycosaminoglycans and Proteoglycans
13 Glycan-Protein Interactions
14 Glycans of Cell Surface Glycoconjugates Perform a Variety of Functions
15 Summary
References
Chapter 2: Cells of the Central Nervous System: An Overview of Their Structure and Function
1 Introduction
2 Neurons
2.1 Neuronal Cell Body
2.2 Cytoskeleton
2.3 Dendrites
2.4 Axon
2.5 Synapse
3 Supporting Cells
3.1 Astrocytes
3.2 Oligodendrocytes
3.3 Microglia
3.4 NG2 Cells (Polydendrocytes)
3.5 Ependymal Cells
4 Extracellular Matrix
5 Concluding Remarks
References
Chapter 3: Synthesis, Processing, and Function of N-Glycans in N-Glycoproteins
1 Introduction
2 N-glycans Are First Born on a Lipid and Then Transferred “En Bloc” onto the Nascent N-glycoprotein in the ER
3 Trimming, Reglycosylation, and Remodeling: There Are Many Ways of N-glycoprotein Processing in the ER and Golgi
4 The Essential Toolbox of a Glycobiologist: A Brief History of the Discovery of N-glycoprotein Biosynthesis Inhibitors and Their Impact on Our Understanding of N-glycan Processing
5 Sweetening the Bond or Sugar-Coating Bad News: Recent Advances in the Role of N-glycans for Virus Infections and Immune Responses
6 Sweet Encounters of Glycoproteins and Glycolipids: N-glycans Affect the Subcellular Distribution and Complex Formation of Enzymes in Glycolipid Biosynthesis
7 Conclusions and Epilogue: The Tale of the Tail That Wags the Dog
References
Chapter 4: Synthesis of O-Linked Glycoconjugates in the Nervous System
1 Introduction
2 Biosynthesis of O-Linked Proteins
2.1 O-GalNAcylation
2.2 O-Mannosylation
2.3 O-GlcNAcylation
2.4 O-Xylosylation
2.5 O-Fucosylation
2.6 O-Glucosylation
3 Biosynthesis of O-Linked Lipids
3.1 Glucosylceramide and Glycosphingolipids
3.2 Galactosylceramide and Glycosphingolipids
3.3 GlcCer and GM3 Synthase Deficiency in Human and Mouse
3.4 Other O-Linked Lipids – New Glucose-Related Lipids
4 Conclusions
References
Chapter 5: Chemistry and Function of Glycosaminoglycans in the Nervous System
1 Introduction
2 Glycosaminoglycan Structure and Chemistry
2.1 Chondroitin Sulfate (CS)
2.1.1 Structure and Chemistry
2.1.2 Synthesis and Modification of CS Chains
2.1.3 CS Proteoglycans (CSPGs) in Brain
2.2 Dermatan Sulfate (DS)
2.3 Heparin
2.4 Heparan Sulfate (HS)
2.4.1 Structure and Chemistry
2.4.2 Synthesis and Modification of HS Chains
2.4.3 Heparan Sulfate Proteoglycans (HSPGs) in Brain
2.5 Keratan Sulfate (KS)
2.6 Hyaluronan (HA)
3 Function of GAGs in the Brain
3.1 GAG Interactions and Binding Partners
3.2 GAG Functions During Brain Development
3.2.1 Neural System Development and Lineage Specification
3.2.2 Brain Patterning
3.2.3 Neurite Outgrowth, Axonal Pathfinding and Migration
3.2.4 Differentiation and Stem-Cell Niche
3.2.5 Synaptic Plasticity
3.3 GAG Function in CNS-Associated Disorders and Injury
3.3.1 Injury Response
3.3.2 Neurological Disorders
3.3.3 Inflammation
3.3.4 Tumorigenesis
4 Concluding Remarks
References
Chapter 6: Structural Analysis of Oligosaccharides and Glycoconjugates Using NMR
1 Introduction
2 Basic NMR Phenomena
3 Chemical Shifts as Structural Probes
4 Through “BOND” and Through “SPACE” Interactions
5 Relaxation and Molecular Motion
6 Paramagnetic Effects as Sources of Long-Distance Information
7 Chemical Exchange: Dynamic Aspects in NMR
8 NMR Tools for Intermolecular Interaction Analysis
8.1 Oligosaccharide–Protein Interactions
8.2 Protein Binding to Glycolipid Clusters
9 Liaisons Between NMR and Computation
References
Chapter 7: Glycans and Carbohydrate-Binding/Transforming Proteins in Axon Physiology
1 Introduction
2 Axon Determination/Early Neuronal Differentiation
3 Axon Guidance
3.1 Axon Guidance by Glycosylated Cell Adhesion Molecules (CAMs)
3.2 Glycosaminoglycans in Axon Guidance
3.3 Galectins and Their Interactions with Guidance Cues in the Adult Olfactory System
4 Axon/Glia Interactions
5 Nerve Impulse Generation/Transmission
5.1 Voltage-Gated Ion Channels
5.2 Voltage-Gated Sodium Channels
5.3 Voltage-Gated Potassium Channels
5.4 Voltage-Gated Calcium Channels
5.5 O-Linked β-N-Acetylglucosaminylation of AIS Proteins
6 Axon Regeneration
7 New Perspective in CNS Regulation Through Glycan-Lectin Interactions in the Microbiota-Gut-Brain Axis
References
Chapter 8: Neurological Consequences of Congenital Disorders of Glycosylation
1 Introduction
2 Classification
2.1 N-Linked Glycosylation Defects
2.2 O-Linked Glycosylation Defects
2.3 Disorders of Glycosylphosphatidylinositol (GPI) Anchor Biosynthesis
2.4 Disorders of Glycosphingolipid (GSL) Glycosylation
2.5 Disorders of Multiple Glycosylation Pathways
2.6 Recently Described CDG with Neurological Presentation
3 Markers/Biochemical Abnormalities
4 Congenital Brain Abnormalities
5 Epilepsy
6 Developmental Delay/Intellectual Disability
7 Ataxia
8 Neuromuscular Presentation
9 Spasticity
10 Autistic Features
11 Extrapyramidal Manifestation
12 Treatment Options
13 Conclusions and New Perspectives
References
Chapter 9: Brain O-GlcNAcylation: From Molecular Mechanisms to Clinical Phenotype
1 Introduction
2 O-GlcNAc Is a Ubiquitous Monosaccharide That Cycles Onto and Off Serine and Threonine
2.1 O-GlcNAc Is Not Elongated to Yield Complex Oligosaccharides
2.2 O-GlcNAc Is Mostly Expressed on the Inside of Cells in Multicellular Organisms
2.3 O-GlcNAc Can Be Dynamically Attached and Removed
3 O-GlcNAc Is Added to Proteins by OGT and Removed by OGA
3.1 Only Two Enzymes Regulate the Cycling of O-GlcNAc
3.2 O-GlcNAc Transferase; a Highly Conserved Glycosyltransferase Present in the Nucleus & Cytosol
3.3 O-GlcNAcase; a Cytosolic O-β-GlcNAc Hydrolase with Neutral pH Optima
4 O-GlcNAc Is Highly Expressed in the Nervous System
4.1 O-GlcNAc Is Found Throughout the Brain
4.2 Thousands of Neuronal Proteins Are Modified by O-GlcNAc
4.3 O-GlcNAc Regulates Diverse Cellular Processes
5 O-GlcNAc Is Essential for Brain Function
5.1 Early and Late Brain Development Depends Upon O-GlcNAc Cycling
5.2 O-GlcNAc Underlies Learning and Memory
5.3 Impaired O-GlcNAc Cycling Contributes to Neurodegenerative Disease
5.4 O-GlcNAc Mediates Central Control of Metabolism
6 Summary and Outlook
References
Chapter 10: Ganglioside Microdomains on Cellular and Intracellular Membranes Regulate Neuronal Cell Fate Determination
1 Introduction
2 Ganglioside Multifunction in Cell Membranes and Intracellular Organelles
3 Ganglioside microdomains for Neuronal Cell Fate Determination
4 GD3-EGFR
5 GD3 Regulates Mitochondrial Dynamics by Interacting with Drp1
6 GD3 Amplifies SOX2 Expression and GM1 Promotes DCX Expression
7 GM1 Binds to Neuronal Gene Promoter Regions
8 Nuclear GM1 Promotes Neuronal Gene Expression
9 Other Gangliosides for NSC Specification
10 Future Studies
References
Chapter 11: Gangliosides and Cell Surface Ganglioside Metabolic Enzymes in the Nervous System
1 Gangliosides
1.1 Ceramide: The Lipid Portion of Gangliosides
1.2 The Oligosaccharide Portion of Gangliosides
2 Gangliosides and Membrane Organization
3 Metabolic Pathways of Gangliosides
4 Plasma Membrane-Associated Enzymes and Ganglioside Pattern
5 Sialidases, Sialyltransferases and Plasma Membrane Sialidase Neu3
6 β-Hexosaminidase and N-Acetylgalactosaminyltransferase
7 β-Glucocerebrosidase
8 β-Galactosidase
9 Membrane Dynamics: A Non-canonical Pathway Involved in the Establishment of the GSL Profile at the Plasma Membrane
10 Conclusions
References
Chapter 12: Neuronal Ganglioside and Glycosphingolipid (GSL) Metabolism and Disease
1 Historical Aspects of Structure, Location and Function of GSLs
2 Significance and Function of Neuronal GGs
3 Intracellular Pathways of GG and GSL Metabolism
4 Emerging Concepts of GSL & GG Metabolism at Organellar Membranes
5 Emerging Topology of Glycolipid Biosynthesis
6 Generation of Cell-Type-Specific Ganglioside Patterns
7 Enzyme Catalysis at Membrane Surfaces
8 GSL Biosynthesis and Salvage Pathways
8.1 Ceramide Synthesis
8.2 Ganglioside Synthesis and Function
9 Inherited Errors of GG Biosynthesis
10 Remodeling and Recycling of Cell Surface Gangliosides
11 Concepts of the Constitutive Degradation of Gangliosides and Glycosphingolipids at ILVs
11.1 Location and Topology of Sphingomyelin, Glycosphingolipids and Ganglioside Catabolism
11.2 Endocytosis of Gangliosides
11.3 Generation of ILVs During Endocytosis and GSL-Catabolism
11.4 Maturation of Intra-Lysosomal Luminal Vesicles (ILVs) and Lipid Sorting
11.5 BMP Formation Contributes Significantly to the Quintessential Negative Surface Charge on ILVs
11.6 Regulation of GG Catabolism and the Removal of Inhibitory Lipids from Intraendosomal Vesicles and ILVs
11.7 Catabolism of Gangliosides at ILVs
11.8 SAPs Are Essential Cofactors for Lysosomal Ganglioside Catabolism
11.9 Membrane Lipid Modifiers Regulate GSL and Ganglioside Catabolism
12 GSL and GG Metabolism and Disease
13 Cascades of Metabolic Errors in LSDs and in Defective GSL Biosynthetic Pathways Generate Complex Pathologies
14 Gangliosides and Glycosphingolipids as Secondary Storage Compounds
15 Accumulation of Lyso-Sphingolipids, Likely Attenuating Lysosomal SL-Catabolism
16 GSL Metabolism and Parkinson Disease
17 Conclusions and Perspectives
References
Chapter 13: Gangliosides in Neurodegenerative Diseases
1 Introduction
2 Essentiality of a-Series Gangliosides
3 Functional Roles of Neuronal Gangliosides: GM1 and Receptors
4 Functional Roles of Neuronal Gangliosides: GM1 and Ion Transport
5 Parkinson’s Disease and Gangliosides
6 Alzheimer’s Disease and Gangliosides
7 Huntington’s Disease and Gangliosides
8 Gangliosides and Additional Neurological Disorders
References
Chapter 14: Functional Impairment of the Nervous System with Glycolipid Deficiencies
1 Introduction
2 GlcCer Synthase-KO Mouse
3 LacCer Synthase-KO Mouse
4 GalCer Synthase-KO Mouse and Sulfatide Synthase-KO Mouse
5 GM3 Synthase-KO Mouse
6 GD3 Synthase-KO Mouse
7 GM2 Synthase-KO Mouse
8 Both GD3S/GM2S-KO Mice (GM3 Only Mice)
9 Both GM3S/GM2S-KO Mice (Ganglioside Null Mice)
10 Diseases Caused by Ganglioside Alterations
10.1 Diseases Caused by Congenital Mutations of Ganglioside Metabolism
10.2 Ganglioside Deficiency in Neurodegenerative Diseases
11 Future Studies
References
Chapter 15: Carbohydrates: Binding Sites and Potential Drug Targets for Neural-Affecting Pathogens
1 Introduction
2 Bacterial Toxins: Lessons Learned
3 Bacterial Infections
4 Viral Infection
5 Latency
6 Neural Problems Induced by Mimicry Between Pathogen and Host
7 Prophylactic Approaches: Under Investigation and in Use
8 Targeting Drugs to the CNS
9 Conclusions
References
Chapter 16: Antibodies to Glycolipids in Guillain-Barré Syndrome, Miller Fisher Syndrome and Related Autoimmune Neurological Diseases
1 Introduction
2 Antibodies to Glycolipid Antigens in GBS and MFS
2.1 IgG Anti-GM1 Antibody
2.2 IgG Anti-GQ1b Antibody
2.3 IgG Anti-GD1b Antibodies
2.4 IgG Antibodies Against GalNAc-GD1a and GM1b
2.5 Antiglycolipid Antibodies in AIDP
2.5.1 Anti-galactocerebroside (Gal-C) Antibody
2.5.2 Anti-LM1 Antibody
3 Animal Models
4 Antibodies to a Combination of Ganglioside and Phospholipid
5 Antibodies to Ganglioside Complexes in GBS
6 Anti-glycolipid Antibodies in CIDP
7 Anti-glycolipid Antibodies in Diseases Affecting the Central Nervous System
7.1 Anti-GQ1b Antibodies in Bickerstaff Brainstem Encephalitis
7.2 Anti-Gal-C Antibodies
8 Future Perspectives
8.1 More Efficient Use of Anti-glycolipid Antibodies as Diagnostic and Prognostic Markers
8.2 To Determine the Clinical Significance of GSCs and the Anti-GSC Antibodies
9 Conclusion
References
Index