Brain Lipids in Synaptic Function and Neurological Disease: Clues to Innovative Therapeutic Strategies for Brain Disorders

379 Pages·2015·53.732 MB·English

by  Jacques Fantini, Nouara Yahi

BRAIN LIPIDS IN
SYNAPTIC FUNCTION
AND NEUROLOGICAL
DISEASE
CLUES TO INNOVATIVE
THERAPEUTIC STRATEGIES
FOR BRAIN DISORDERS
Jacques Fantini
Molecular Interactions in Model and Biological Membranes Laboratory,
Faculty of Science and Technology, Marseille, France
nouara Yahi
Molecular Interactions in Model and Biological Membranes Laboratory,
Faculty of Science and Technology, Marseille, France
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Copyright © 2015 Elsevier Inc. All rights reserved.
Cover image: Formation of α-helical ion channels by Aβ. At appropriate Aβ/GM1 ratios, Aβ monomers
may bind to cell surface GM1 and subsequently fold into an α-helical structure. The insertion of α-helical Aβ in
lipid raft domains enriched in cholesterol (chol) is followed by the oligomerization of Aβ into an oligemeric annular
pore permeable to calcium. This sequence of events is summarized in the top panel; the structure of the oligomeric
Aβ channels is shown in the images below (from left to right, top view, lateral view, and bottom view); the surface
potential of the models is colored in red (negative), blue (positive) or white (apolar regions).
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ISBN: 978-0-12-800111-0
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Dedication
Dedicated to the memory of our wonderful friend and colleague, Nicolas Garmy, who left us
too soon. How we wish, how we wish you were here…
About the Authors
Jacques Fantini was born in France in binding domain (SBD) in proteins with no
1960. He has more than 30 years of teaching sequence homology but sharing common
and research experience in biochemistry and structural features mediating sphingolipid
neurochemistry areas. Since 1998, he has been recognition. The SBD is present in a broad
Professor of Biochemistry and an honorary range of infectious and amyloid proteins, re-
member of the Institut Universitaire de France. vealing common mechanisms of pathogen-
Nouara Yahi was born in France in 1964. esis in viral and bacterial brain infections
She has accumulated 25 years of fundamental and in neurodegenerative diseases. Their
research and teaching experience in virol- current research is focused on the molecular
ogy and molecular biology areas. She is cur- organization of the synapse in physiological
rently Professor of Biochemistry and leader and pathological conditions. Jacques Fan-
of the research group Molecular Interactions tini and Nouara Yahi have been working
in Model and Biological Membrane Systems. together since 1991 and have copublished
This group is internationally recognized for 72 articles referenced in PubMed and nine
studies of lipid–lipid and lipid–protein inter- patent applications. Jacques Fantini is the
actions pertaining to virus fusion, amyloid author/coauthor of 167 articles (PubMed),
aggregation, oligomerization, and pore for- with 5800 citations and an H-index of 42.
mation. Nouara Yahi is the author/coauthor of 82
Together, Nouara Yahi and Jacques Fantini articles (PubMed), with 3500 citations and
have discovered the universal sphingolipid- an H-index of 35.
xi
Preface
Lipids are the most abundant organic rules and just enough vocabulary to guide
compounds found in the brain, accounting the traveler throughout foreign countries.
for up to 50% of its dry weight. The brain Our ambition with this book is to offer a
lipidome includes several thousand distinct comprehensive overview of brain lipid struc-
biochemical structures whose expression tures and to explain how these lipids control
may greatly vary according to age, gender, synaptic functions through a network of li-
brain region, and cell type, as well as subcel- pid–lipid and lipid–protein interactions. We
lular localization. In synaptic membranes, also explain the role of major brain lipids
brain lipids specifically interact with neuro- (cholesterol and sphingolipids) in the patho-
transmitter receptors and control their activ- genesis of neurodegenerative diseases, in-
ity. Moreover, brain lipids play a key role in cluding Alzheimer’s, Creutzfeldt–Jakob, and
the neurotoxicity of amyloidogenic proteins Parkinson’s. We show that these diseases
involved in the pathophysiology of neuro- involve strikingly common mechanisms of
logical diseases. pathogenesis that are also used by pathogens
Biochemistry provides the ultimate mech- to invade brain cells. This concerns especially
anistic explanation of most biological pro- HIV-1 and amyloid proteins, as well as bacte-
cesses. Obviously this information may not rial toxins and amyloid oligomers.
be sufficient to understand some biologi- The book has been written to provide a
cal functions, which also involve integrated hands-on approach for neuroscience gradu-
networks at different levels, from the cell to ate students. Biochemical structures are dis-
the body. However we rarely need to bring sected and explained with molecular models.
biology to the subatomic level. Studying Moreover, we propose a step-by-step guide
biochemistry is not boring, provided that it to memorize and draw the biochemical struc-
is taught with the aim of answering clearly ture of brain lipids, including cholesterol and
enunciated questions. What would be the complex gangliosides. To conclude the book,
rationale of learning an endless list of mo- we present new ideas that can drive inno-
lecular structures that we would probably vative therapeutic strategies based on the
never meet in a scientist’s life? As professors knowledge of the role of lipids in brain dis-
of biochemistry, we did in this book what orders.
we do in our teaching activity: provide the
molecular basis required for understanding Jacques Fantini
biological functions, not more, not less. It is Nouara Yahi
just like learning a language: good grammar Septèmes-les-Vallons, France
December 1, 2014
xiii
Acknowledgments
We would like to thank all the scientists, France) and the scientific advisors who in-
colleagues, and friends who supported us terviewed us, Claude Bernard and François
during the course of our scientific career, es- Jacob, for supporting the young scientists
pecially Francisco Barrantes, Luc Belzunces, that we were before our names appeared in
Pierre Burtin, Henri Chahinian, Ahmed PubMed.
Charaï, Caroline Costedoat, Patrick Cozzone, It has been a pleasure to work on this book
Olivier Delézay, Coralie Di Scala, Assou El with Kristi Anderson and Natalie Farra from
Battari, Francisco Gonzalez-Scarano, Claude Elsevier/Academic Press.
Granier, Nathalie Koch, Xavier Leverve, Finally we thank our beloved son Driss,
André Jean, Jean-Marc Sabatier, Louis Sarda, nephews Fahem and Lounis, sister Djamila,
and Catherine Tamalet. brother-in-law Jean-Philippe, and our late
We also thank the Fondation Marcel parents. Your love is our life.
Bleustein-Blanchet pour la Vocation (Paris,
xv
C H A P T E R
1
Chemical Basis of Lipid Biochemistry
Jacques Fantini, Nouara Yahi
O U T L I N E
1.1 Introduction 1 1.5.4 Biochemistry of Unsaturated
Fatty Acids 9
1.2 Chemistry Background 2
1.5.5 Glycerolipids 11
1.3 Molecular Interactions 3 1.5.6 Sphingolipids 14
1.5.7 Sterols 23
1.4 Solubility in Water: What Is It? 4
1.6 Biochemical Diversity of
1.5 Lipid Biochemistry 6
Brain Lipids 24
1.5.1 Definition 6
1.7 A Key Experiment: Lipid Analysis
1.5.2 Biochemistry of Fatty Acids 7
by Thin Layer Chromatography 25
1.5.3 Biochemistry of Saturated
Fatty Acids 7 References 26
1.1 INTRODUCTION
Biochemistry (biological chemistry, chemical biology, or chemistry of living systems) is a
scientific discipline that arose during the nineteenth century when progress in organic chem-
istry allowed the study of biological functions at the molecular level. It comprises several
domains, each with its own purpose and more or less specific methods of investigation. The
most important include the following:
• Enzymology: the study of biological catalysts (chiefly enzymatic proteins referred to as
enzymes, but also catalytic RNAs called ribozymes)
• Molecular biology: the study of informational macromolecules (DNA, RNA, and, in the
case of neurodegenerative diseases, proteins)
• Structural biology: the study of the shapes embraced by all these macromolecules
(described at the atomic level) and the molecular interactions controlling the formation of
functional superstructures (e.g., ribosomes).
Brain Lipids in Synaptic Function and Neurological Disease. http://dx.doi.org/10.1016/B978-0-12-800111-0.00001-1
Copyright © 2015 Elsevier Inc. All rights reserved.
1
2 1. ChEmICaL BasIs Of LIpId BIOChEmIsTry
These domains share the same disciplinary field, biochemistry, whose goal is to under-
stand the molecular nature and functioning of living organisms. Should you want to study
the properties of living matter at the subatomic level in detail, you must leave the field of biol-
ogy to enter quantum chemistry. Therefore, biochemistry is the ultimate level of investigation
for the study of biological functions. To study phenomena at this molecular scale requires a
basic knowledge of chemistry. The study of brain lipids and their role in synaptic function
and neurodegenerative disorder does not escape this rule.
1.2 CHEMISTRY BACKGROUND
Because lipids are chiefly defined on the basis of their insolubility in water, you must first
understand the key features of a molecule that is soluble in water, and then try to figure out
why lipid molecules are not. It is not a simple task, and we will restrict our discussion to basic
rules that emerge from clear-cut chemical concepts. Studying the water molecule will be help-
ful to address these fundamental concepts. As encouragement to take the time to carefully
read this section (in which we do not present any lipid structure yet), be aware that mastering
these basic notions will give you a number of universal keys for entering the complex world
of biological structures with confidence. Hopefully it will convince you of how logical this
world is indeed.
Water is by far the most abundant molecule found in living organisms, accounting for ap-
proximately 70% of our own weight. Nevertheless, it is neither specific (water is also found
outside living creatures) nor representative (it lacks carbon atoms that are the hallmark of
organic molecules). Its chemical formula H O indicates that it is composed of two hydrogen
2
atoms and one oxygen atom. Given that the valence of these atoms is 2 for oxygen and 1 for
hydrogen, the chemical bonds of the water molecule can be formed in only one way: the oxy-
gen atom establishes a bond with each hydrogen atom. Therefore, the O─H bond is the only
type of chemical bond in the water molecule. This covalent bond results from the sharing of
a pair of electrons, one given by oxygen, the other by hydrogen. Now, where are these elec-
trons located? An intuitive answer could be “somewhere between the oxygen and the hydro-
gen atoms.” If both atoms were identical (e.g., in the hydrogen molecule H─H), then the
highest probability of finding the electrons of the chemical bond would be at an equal distance
from each atom. However, such is not the case for the O─H bond because oxygen is more
“electro-attractive” than hydrogen. As a consequence, the electrons that form the O─H bond
are closer to the oxygen atom than to hydrogen. Thus, the O─H bond is polarized, whereas
the H─H bond is not. This characteristic is how we distinguish heteropolar polarized bonds
linking two distinct atoms X─Y versus homolar nonpolarized bonds linking two identical at-
oms X─X. The asymmetrical distribution of the electron pair in the O─H bond greatly benefits
the oxygen atom that is surrounded by an excess of electrons, whereas the electron cloud of
the hydrogen atom is in deficit. Both surplus and deficit can be energetically quantified, but
we will restrict our discussion to a qualitative analysis: the excess of electrons around the
oxygen atom creates a partial negative charge that is noted d−. Why a partial and not a real
negative electrical charge? Because the O─H bond still exists. It is only when the chemical
bond breaks that the oxygen atom takes full control of the electron pair (i.e., it recovers its
own electron and steals the one provided by hydrogen). In this case, the oxygen atom bears a
1.3 mOLECULar INTEraCTIONs 3
TABLE 1.1 Linus pauling’s Electronegativity scale for Biochemistry students
Atom Relative electronegativity
Hydrogen (H) 2.1
Carbon (C) 2.5
Nitrogen (N) 3.0
Oxygen (O) 3.5
bona fide negative charge and is now written as O–. If one applies the same reasoning, the hy-
drogen atom of the O─H bond possesses a partial positive charge that is noted d+. In summary,
the O─H bond is characterized by the presence of two opposite partial charges. Correspond-
ingly, we can write this bond , which means that the O─H bond is polarized and the
oxygen atom attracts to itself the electrons pair of the chemical bond. We say that oxygen is more
electronegative than hydrogen. Nobel Prize winner Linus Pauling was the first to define an
electronegativity scale for all atoms.1 In this chapter, we will simply mention the electronegativ-
ity of the four most important atoms in biochemistry: C, H, O, and N (Table 1.1). When neces-
sary, we will extend this table to less abundant but biologically significant atoms such as P or S.
Should you be marooned on a desert island, you will need to know these values by heart if
you want to recover an almost complete knowledge in biochemistry. Indeed, this table allows
you to predict both the presence and distribution of partial charges in any molecule contain-
ing these atoms. For instance, we can see that oxygen has a higher electronegativity than
carbon (respectively, 3.5 and 2.5). Thus, the C─O bond is polarized and is noted: .
Similarly, the electronegativity of nitrogen is higher than that of hydrogen, so that the N─H
bond is polarized: . The C─N bond is also polarized: . However, when it
comes to C and H, the difference of electronegativity falls below 0.5 so that the C─H bond is
not significantly polarized (also due to the intrinsic low electronegativity of H and C). All you
need to know in chemistry to understand the concepts developed in this book is based on the
electronegativity of a handful of atoms that constitute the living matter.
1.3 MOLECULAR INTERACTIONS
Over the years biochemistry has become the science of molecular interactions between bio-
molecules. We will consider the water molecule as a guide to explore one of the most intrigu-
ing properties of biomolecules, that is, their capacity to assemble with one another to form
complex (and generally transient) structures. Such molecular complexes are noncovalent in
nature because building and breaking covalent bonds requires a high energy input. The hy-
drogen bond (H-bond) is probably the most famous noncovalent interaction able to stabilize
a molecular complex at a minimal energy cost. H-bonds are involved in the reversible asso-
ciation of the two antiparallel strands of the DNA double helix. The H-bond also ensures the
cohesion of water molecules and explains why so much energy (100°C) is required to separate
these molecules when passing water from liquid to gaseous state. The H-bond is a bond of
electrostatic type that should not be confused with an electrostatic bond between two oppo-
site electric charges (e.g., Na+ and Cl– ions). It usually occurs between an electronegative atom
4 1. ChEmICaL BasIs Of LIpId BIOChEmIsTry
FIGURE 1.1 Hydrogen bond (H-bond) network between water molecules. Hydrogen bonds are indicated by
dotted lines (in blue on the left panel). The right panel shows the results of molecular dynamics simulations of the
hydrogen bond network involving four HO molecules in the same orientation as in the scheme of the left panel
2
(obtained with the HyperChem software).
having at its periphery a free electron pair (most often N or O in biology) and a d+ hydrogen
covalently bound to an electronegative atom (e.g., OH or NH). Both atoms involved in an H-
bond move closer to each other due to the attraction of the d+ hydrogen atom by the electron
pair of the electronegative atom. It is precisely this type of interaction that occurs between
two water molecules (Fig. 1.1).
One differentiates the H-bond donor group (the one that provides the hydrogen atom)
and the acceptor group (the oxygen atom that provides the electron pair). Correspondingly,
the water molecule has two H-bond donor groups (two hydrogen atoms) and two acceptor
groups (two pairs of peripheral electrons on oxygen). Each water molecule can thus form a
maximum of four H-bonds with its neighbors. Thus, the maximum coordination number of
water is equal to 4. In practice, this value of 4 is reached only in water in the form of ice. In
liquid water at 25°C, it is still as high as 3.7, indicating a strong cohesion of liquid water at
this temperature (vaporization requires much more energy, i.e., 100°C). Separating the water
molecules to pass from the liquid state to the gaseous state implies breaking all H-bonds
connecting water molecules in a given volume of water. Although each individual H-bond
is of low energy, their large number compensates for this energy weakness, which explains
why it is necessary to provide a high amount of energy (equivalent to 100°C) to reach the
temperature of vaporization of water. In addition to the H-bonds, several other types of
molecular interactions are described in subsequent chapters (in particular London disper-
sion forces that are involved in various lipid assemblies, including biological membranes,
see Chapter 2).
1.4 SOLUBILITY IN WATER: WHAT IS IT?
A compound is soluble in water if it is able to surround itself with water so that the mol-
ecules no longer have any contact between themselves. This compound is then referred to as
a “solute.” Solute molecules interact with water molecules by establishing hydrogen bonds
with them. Therefore, a compound is water-soluble if it possesses at its surface chemical
groups capable of forming H-bonds. For instance, the urea molecule (Fig. 1.2), which can