Brain Lipids in Synaptic Function and Neurological Disease (eBook)

Clues to Innovative Therapeutic Strategies for Brain Disorders

Jacques Fantini, Nouara Yahi (Autoren)

eBook Download: PDF | EPUB

2015 | 1. Auflage
398 Seiten
Elsevier Science (Verlag)
978-0-12-800492-0 (ISBN)

Infos

Lipids are the most abundant organic compounds found in the brain, accounting for up to 50% of its dry weight. The brain lipidome includes several thousands of distinct biochemical structures whose expression may greatly vary according to age, gender, brain region, cell type, as well as subcellular localization. In synaptic membranes, brain lipids specifically interact with neurotransmitter receptors and control their activity. Moreover, brain lipids play a key role in the generation and neurotoxicity of amyloidogenic proteins involved in the pathophysiology of neurological diseases. The aim of this book is to provide for the first time a comprehensive overview of brain lipid structures, and to explain the roles of these lipids in synaptic function, and in neurodegenerative diseases, including Alzheimer's, Creutzfeldt-Jakob's and Parkinson's. To conclude the book, the authors present new ideas that can drive innovative therapeutic strategies based on the knowledge of the role of lipids in brain disorders. - Written to provide a 'hands-on' approach for readers - Biochemical structures explained with molecular models, and molecular mechanisms explained with simple drawings - Step-by-step guide to memorize and draw lipid structures - Each chapter features a content summary, up-to-date references for additional study, and a key experiment with an explanation of the technique

Jacques Fantini was born in France in 1960. He has over 30 years of teaching and research experience in biochemistry and neurochemistry areas. Since 1998, he is professor of biochemistry and honorary member of the 'Institut Universitaire de France'. He has demonstrated the implication of glycolipids in the attachment and fusion of HIV-1 with the plasma membrane of target cells, and has published several important articles in this field. He is an active member of the research group 'Molecular Interactions in Model and Biological Membrane Systems' led by Nouara Yahi. This group is internationally recognized for studies of lipid-lipid and lipid-protein interactions pertaining to virus fusion, amyloid aggregation, oligomerization and pore formation. Together with Nouara Yahi, Jacques Fantini has discovered the universal sphingolipid-binding domain (SBD) in proteins with no sequence homology but sharing common structural features mediating sphingolipid recognition. The SBD is present in a broad range of infectious and amyloid proteins, revealing common mechanisms of pathogenesis in viral and bacterial brain infections, and in neurodegenerative diseases. His current research is focused on the molecular organization of the synapse in physiological and pathological conditions. Jacques Fantini is the author/co-author of 175 articles (PubMed), with 7500 citations and a H-index of 49. He has also published 4 patent applications. Jacques Fantini personal web site: https://jfantini.jimdo.com

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Lipids are the most abundant organic compounds found in the brain, accounting for up to 50% of its dry weight. The brain lipidome includes several thousands of distinct biochemical structures whose expression may greatly vary according to age, gender, brain region, cell type, as well as subcellular localization. In synaptic membranes, brain lipids specifically interact with neurotransmitter receptors and control their activity. Moreover, brain lipids play a key role in the generation and neurotoxicity of amyloidogenic proteins involved in the pathophysiology of neurological diseases. The aim of this book is to provide for the first time a comprehensive overview of brain lipid structures, and to explain the roles of these lipids in synaptic function, and in neurodegenerative diseases, including Alzheimer's, Creutzfeldt-Jakob's and Parkinson's. To conclude the book, the authors present new ideas that can drive innovative therapeutic strategies based on the knowledge of the role of lipids in brain disorders. - Written to provide a "e;hands-on"e; approach for readers- Biochemical structures explained with molecular models, and molecular mechanisms explained with simple drawings- Step-by-step guide to memorize and draw lipid structures- Each chapter features a content summary, up-to-date references for additional study, and a key experiment with an explanation of the technique

Textauszug

Chapter 2

Brain Membranes

Jacques Fantini

Nouara Yahi

Abstract

In this chapter you will learn why and how lipids have the unique capability to self-organize into various superstructures, from micelles to membrane bilayers. Basic principles of the physicochemical properties of lipids are explained in simple terms. We offer a didactic step-by-step overview of fundamental concepts such as the hydrophobic effect, lipid molecular shapes and packing parameters, melting temperature, membrane fluidity, lipid phases and miscibility, hexagonal organization, membrane asymmetry, and curvature effects. The noncovalent attractive forces that stabilize specific lipid–lipid complexes and larger lipid assemblies are carefully described. The role of cholesterol in both liquid-disordered (Ld) and liquid-ordered (Lo) phases of the plasma membrane is also discussed. Schematic models of membranes with increasing complexity gradually emerge from this overview, leading to the final description of the plasma membrane of glial cells (oligodendrocytes, astrocytes) and neurons that express specific and distinct patterns of glycosphingolipids in their lipid raft domains.

Keywords

lipid

plasma membrane

lipid raft

hydrogen bond

London forces

bilayer

micelle

packing parameter

lipid polymorphism

hexagonal phase

Outline

2.1 Why Lipids are Different from all Other Biomolecules 29

2.2 Role of Structured Water in Molecular Interactions 30

2.3 Lipid Self-Assembly, a Water-Driven Process? 31

2.4 Lipid–Lipid Interactions: Why Such a High Specificity? 35

2.4.1 Melting Temperature of Lipids 36

2.4.2 The Molecular Shape of Lipids 38

2.5 Nonbilayer Phases and Lipid Dynamics 45

2.6 The Plasma Membrane of Glial Cells and Neurons: The Lipid Perspective 45

2.7 Key Experiments on Lipid Density 49

References 49

2.1. Why lipids are different from all other biomolecules

The famous Francis Crick’s adage, “If you want to understand function, study structure,” does not apply to lipids. Observe and dissect the structure of phosphatidylcholine (PC) as long as you want, you will not understand how plasma membranes are organized and function. The reason is that lipids do not act alone but cooperate to form ordered molecular assemblies that have acquired specific functional properties. Here the whole is not only more than the sum of its parts, the whole creates the functions the parts totally lack. In first approximation, this unique feature can be compared to a brick (a single lipid molecule) in a wall (here representing the membrane, interestingly historically referred to as the cell wall). To begin, we will keep in mind this rough analogy while explaining why lipid molecules can self-assemble into various architectural motifs.

2.2. Role of structured water in molecular interactions

In biochemistry, when one molecule interacts with another one to form a complex, great attention is given to the chemical groups that are physically involved in the interaction. These chemical groups constitute the so-called “binding site,” a three-dimensional domain of a molecule that is specifically devoted to the binding of another one. Such binding sites should be readily accessible to the molecular partner with which it is promised to interact. Let us consider the interaction between two proteins circulating in a biological fluid. Each of these proteins displays a binding site at its periphery. In the water environment in which these proteins circulate, these peripheral binding sites are first occupied by water molecules. When both proteins come in close contact, bound water molecules leave the binding domains so that the proteins can interact through noncovalent bonds (Fig. 2.1).

Figure 2.1 Dehydration precedes binding reactions in water.
Consider two proteins, A and B, in solution in water (water molecules of the bulk solvent are represented as blue disks). Each of these proteins has a complementary binding site for the other one, yet initially both binding sites are covered with a layer of bound water (represented as purple disks). The binding reaction is possible only if these water molecules initially interacting with the binding sites are displaced (arrows) and redistributed randomly in the bulk solvent, thereby inducing an increase of entropic disorder. Note that the water molecules bound to regions of proteins A and B not involved in binding (represented as dark blue disks) are not affected by the process.

In this respect, the binding process can be decomposed in two phenomena: (1) the destructuration of numerous water molecules that were initially associated with each binding site through a network of hydrogen bonds, and (2) the formation of a new set of noncovalent interactions between the binding sites of each protein partner.1 Both mechanisms contribute to the energy of association required to form the complex. We have learned from thermodynamics that the Gibbs free energy change associated with a chemical reaction (i.e., ∆G) takes into account both mechanisms. On one hand, the departure of numerous water molecules from each binding site generates a significant molecular disorder, quantified as an entropy increase (∆S). Disorder is energy, because going back to the order state requires energy (e.g., teenagers who let the disorder progressively develop in their bedroom know how hard it is to clean it). On the other hand, the noncovalent bonds that are formed between both binding sites contribute to the whole energy of interaction, because you would need energy to break them. This enthalpic contribution of the binding is expressed by the ∆H term of the classical equation ∆G = ∆H – T∆S where T is the absolute temperature (expressed in Kelvin, allowing ∆G to be expressed in joules per moles or more representatively in kJ mol–1). It is clearly beyond the scope of this book to dwell further on this famous thermodynamic equation. Let us just remark that the free energy change ∆G of any spontaneous reaction must have a negative value. In this respect, the sign of ∆H indicates whether the binding process is chiefly enthalpy-driven or entropy-driven. Schematically, enthalpic binding results from specific molecular interactions, such as hydrogen bonds that require a perfect adjustment of both ligands (∆H < 0). In contrast, entropic binding is far less specific because it relies primarily on the disorder created in water molecules surrounding the ligands. In practice, “pure” enthalpic or entropic binding does not exist because both contribute to the binding reaction. Indeed, whatever the sign of ∆H (positive or negative), it is clear that a significant value of the entropy change ∆S ensures that ∆G is negative and high, which is particularly critical when ∆H is positive. In this case ∆G will be negative only if the entropic term ∆S is sufficiently high, which will occur if there is enough disorganization of water molecules (Fig. 2.1). Moreover, even for binding reactions with a negative ∆H, it is important that the binding process is associated with the displacement of a maximal number of bound water molecules, which will further increase ∆S and thus ∆G. This information gives a realistic idea of the entropic contribution to binding reactions. Lipid–lipid interactions will not escape this important contribution of water molecules, and as we will see next, water will even do more.

2.3. Lipid self-assembly, a water-driven process?

Because lipids are mostly apolar molecules, they are not particularly inclined to accommodate water molecules. However, this statement can be viewed as a tautology because lipids are precisely defined on the basis of their insolubility in water (see Chapter 1). In fact the situation is more complex because in addition to their large apolar, water-insoluble domain, lipids also display a polar head group. Hence, lipid behavior is typically amphipathic, their apolar part exhibiting hydrophobic properties that contrast with their hydrophilic polar head group. Before going further, one should understand that the terms apolar and hydrophobic, and similarly polar and hydrophilic, cannot be used as synonyms. Apolar refers to an intrinsic property of chemical group due to the weak electronegativity of its atoms (chiefly C and H). Because an apolar group cannot form hydrogen bonds with water molecules, it does not interact with water and hence it will have a hydrophobic behavior. On the opposite, a polar group contains electronegative atoms (O, N) often linked to hydrogen (–O–H and –N–H groups), that, due to the...

Produkt-Details

• Erscheint lt. Verlag: 12.5.2015
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Neurologie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Physiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Humanbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zoologie
• Themenwelt: Technik
• ISBN-10: 0-12-800492-4 / 0128004924
• ISBN-13: 978-0-12-800492-0 / 9780128004920