Neurodegeneration: Metallostasis and Proteostasis: Volume 7 (Drug Discovery Series) - Hardcover

Hardcover

ISBN 10: 1849730504 ISBN 13: 9781849730501

Publisher: Royal Society of Chemistry, 2011

Synopsis

This exemplary book gives an up-to-date perspective on the role of metal ions in neurodegeneration.

About this title

About the Author

Danilo Milardi obtained a degree in Industrial Chemistry from the University of Catania before going on to obtain a PhD in protein thermodynamics. He has been involved in various MIUR projects concerned with protein thermodynamics and in 1997 obtained a fellowship of the University of Catania in collaboration with Cyanamid S.p.A. He currently works as research scientist at the Italian Consiglio Nazionale delle Ricerche (CNR) - Instituto di Biostrutture e Bioimmagini. He also has extensive experience in teaching and the coordination of research projects. Dr Milardi was a member of the organizing committee of the 8th National Meeting of the Italian Liquid Crystal Society and is the author of 41 scholarly papers and 60 communications to national and international congresses. Enrico Rizzarelli is currently a professor in the Dipartimento di Scienze Chimiche at the UniversitÓ di Catania. His main research Interests include: molecular recognition processes assisted by metal ions; synthesis, characterization and biological activity of copper(II) coordination compounds; protein misfolding diseases and metal ions, and model systems of metal enzymes with antioxidant activities. He is a member of numerous scholarly societies and has been an invited speaker or chair at many national and international meetings. He regularly referees manuscripts for numerous international journals and has authored about 220 papers himself. He has co-authored and guest edited several key books and been the author of three European patents. Enrico Rizzarelli also refereed research projects on the behalf of Italian and international research bodies.

From the Back Cover

Since Alois Alzheimer described the results of his postmortem studies in 1906, significant strides have been made in understanding the pathogenesis of neurodegenerative diseases. Substantial evidence has accumulated indicating that diverse neurodegenerative disorders might share a common pathological mechanism: the misfolding, aggregation and accumulation of proteins (termed "amyloid") in the brain. Metal ions have long been thought to catalyze protein misfolding initiating a cascade of events resulting in oxidative damage and neurodegeneration. They have, consequently, been seen as a suitable pharmacological target. However, drugs aimed at simply removing excess metals or interfering in amyloid deposition were unsuccessful and scientists have been forced to review the classical hypothesis. The latest advances suggest that deficiencies in protein homeostasis may lead to cell dysfunction and disease. Furthermore, small molecules with the potential to control metal homeostasis, or metallostasis, are expected to provide the framework for the design of novel proteostasis regulators. This book provides an up-date on the latest developments in this fast moving field. Traditional views concerning the relationship between the physio-pathological cycles of copper, zinc, iron, aluminium and the evolution of life, are compared with emerging ideas in the neuroscience of metal ions. Topics covered emphasize the importance of metals and oxidation chemistry to neuroscientists as well as providing a wider, multidisciplinary background to chemists who are attracted by these fascinating subjects. The text starts with a chapter on chemical evolution, the brain and metallomics which describes the brain's natural defences to adverse conditions. It then goes on to cover the chemistry and biology of proteostasis, environmental factors, and the role played by membranes in protein misfolding. The remaining chapters cover the role of metals and oxidative stress in Alzheimer's Disease, Parkinsonism, ALS and other neurodegenerative diseases. The book is suitable for academics, those working in industry, and postgraduate students.

Excerpt. © Reprinted by permission. All rights reserved.

Neurodegeneration

Metallostasis and Proteostasis

By Danilo Milardi, Enrico Rizzarelli

The Royal Society of Chemistry

Copyright © 2011 Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-84973-050-1

Contents

Chapter 1 An Introduction to the Brain and its Biological Inorganic Chemistry R. J. P. Williams and J. J. R. Fraústo da Silva, 1, 
Chapter 2 Chemistry and Biology of Proteostasis M. J. Saaranen and L. W. Ruddock, 18, 
Chapter 3 Proteostasis as a Signaling Device and Therapeutic Target S. Cenci and R. Sitia, 46, 
Chapter 4 Amyloid Channel Modulation by Metal Ions B. L. Kagan, 69, 
Chapter 5 Metal Ions and the Clearance of Misfolded Proteins G. Grasso, D. La Mendola and D. Milardi, 83, 
Chapter 6 The Inorganic Side of Alzheimer's Disease G. Pappalardo, D. Milardi, E. Rizzarelli and I. Sovago, 112, 
Chapter 7 Zinc, Copper, Neurotrophic Factors and Neurodegeneration G. Amadoro and P. Calissano, 141, 
Chapter 8 Biological Metals: Metallostasis and Alzheimer's Disease A. Rembach, J. A. Duce, L. A. O'Sullivan, R. E. Tanzi and A. I. Bush, 152, 
Chapter 9 The Role of Iron in Neurodegeneration F. A. Zucca, F. A. Cupaioli and L. Zecca, 174, 
Chapter 10 Aluminium in Neurodegenerative Diseases S. Bolognin and P. Zatta, 212, 
Chapter 11 Metal Toxicity and Metallostasis in Amyotrophic Lateral Sclerosis H. L. Lelie, J. P. Whitelegge, D. R. Borchelt and J. S. Valentine, 226, 
Chapter 12 Copper and Prion Protein Function: A Brief Review of Emerging Theories of Neuroprotection G. L. Millhauser, 249, 
Subject Index, 259, 

CHAPTER 1

An Introduction to the Brain and its Biological Inorganic Chemistry

R. J. P. WILLIAMS AND J. J. R. FRAÚSTO DA SILVA

1.1 Introduction

The brain is a complex structure, composed of many zones organised as compartments that are apparently isolated by the manner of folding of the outer structure and by the packing and types of cells in the structures (Figure 1.1 and Table 1.1). The functions of the compartments and the chemicals in them, distinguished by staining, apart from their physical characteristics, give ways of delineating them. It is also possible to describe the zones by the size of their differentiated electrical responses stimulated by actual or experimental outside events. A more detailed level of division of the description of the zones is by the cellular and membrane structures and their differences. There are two major classes of cell types in all zones, neurons and glia, and we shall describe them in turn, at first as if they were independent cell types. Each neuron appears to be separated from all others spatially and by several surrounding glial cells except for deliberate connection made between neurons at synaptic junctions. In this general introduction we draw special attention to the part played by metal ions and their enzymes.

1.2 The Structure of Neurons

The simple description of a neuron is that it is made of a central nuclear body of ill-defined shape but considerable volume, see Figure 1.2(a) and (b), with long very thin tubular extensions called axons. The extensions have termini, which can act as donors or acceptors of chemicals in the message system of brain states and are seen as somewhat bulbous regions, see Figure 1.2(c). The physical structure of the central region of the neuron (the soma) is that of a eukaryotic cell and has the usual compartments of organelles and vesicles. The axons are structured internally by conventional fibrous proteins, including tubulins capable of allowing transfer of vesicles from the central body to the bulbous termini. The membranes of the axons in the brain cover long stretches between "nodes of Ranvier", Figure 1.3, where there are active channels and pumps for Na and K ions. The protection is provided by myelin proteins produced by oligodendrocytes, a special kind of glial cell. In general it is considered that the axons are just long-range connections between the central region and the bulbous termini. The major components of the liquid in them are generally considered to be of the same ionic content as the cytoplasm, but have few, if any, enzymes and little metabolic activity. However, the nodal membranes have ion gates and ATP-ases as pumps. We return to the chemical composition at termini later since these bulbous zones have a concentration of vesicles of differing chemical contents. The outer membranes here have the usual contents and properties of the eukaryotic cell, being able to exo- and endocytose, and have numerous enzymes on the surfaces able to act in donor or acceptor capacities, especially as channels and pumps. The axons are able to grow independently by cell multiplication or replication. The cells are physically surrounded by extracellular fluid, which in the brain is a special fluid separated from the blood by a blood–brain barrier. Although the whole brain is aerobic and neurons require oxygen they are also supported with some nutrients by glial cells. There is also extensive connective tissue composed of proteins and polysaccharides to maintain structure.

1.3 The Chemical Activity of Neurons

The main chemical activities of the nerve cell are simply divided. The central region is one major supplier of small and large chemicals and energy to its axons and then to the bulbous termini. The axons, at active nodes, seem only to require a large amount of energy to maintain their electrical activity, which is their dominant function. The activity is a self-sustaining relay of electrostatic ion flow of such a character that it allows depolarisation and repolarisation due to the flow of Na+/K+ ions from inside to outside, and its reversal, see Figure 1.3. On allowing initial depolarisation through channels the wave of depolarisation travels along the axon as an electrical signal, but the axon recovers immediately by pumping the ions back into itself. It is very important, therefore, that both the internal cytoplasmic and the external concentrations of the fluids, see Table 1.2, are very precisely fixed. The maintenance (homeostasis) of Na+ and K+ ions is a critical factor in nerve and brain chemistry. Note that it is standard hospital practice to monitor these levels in humans for any sign of weakness, which could ultimately affect the brain.

The depolarisation wave travels to the termini at the synapse where it activates donor events. The donation is of transmitters, which travel to acceptor centres in the opposing neuron of an adjacent synapse after release from storage vesicles. The chemistry involved thereafter is complex. We shall therefore leave aside the chemical activities in the axons while we describe those of the bulbous zones. These terminal zones have outer membranes, which directly or indirectly are stimulated by the depolarisation wave to allow calcium ion entry into the cytoplasm of the bulb. In turn the calcium ions cause a filamentous action to move the vesicles holding transmitters to the cell membrane where they discharge either their small molecules or ions into the extracellular fluid, directed as much as is possible toward a bulbous zone of a receptor cell. This cell then initiates a second Na+/K+ wave down its axon, using the ion gradients. The outside concentrations are shown in Table 1.2 while the inside concentrations are: K+ approx. 100 and Na+ approx. 5 mEq per kg H2O. The small molecules and ions, e.g. Zn2+, are both called trans mitters. The donor bulbous region must now quickly recover its resting chemical content by filling its depleted stores in vesicles; see also Glial Cells. The energy required for the passage of a signal is considerable.

The chemical content of particular interest lies in the packaging of transmitters in the vesicles, which can contain a vast number of different organic and inorganic ions. Different neurons have different vesicle contents. Analysis indicates that these include both positive, e.g. adrenaline (epinephrine), and negative, e.g. glutamic acid, or even zwitterions, e.g. γ-amino butyric acid and small cations such as Zn2+. We have listed some of them in Table 1.3. Note some of the brain amino acids are D- not the conventional L- of the main body. The peptides may not be present in a simple immediately available form, but may be part of larger peptides or proteins, e.g. chromogranin A, which are hydrolysed on external release to give statin-like peptides. The differently charged transmitters cannot be stored without molecules carrying the opposite charge. Adrenaline is stored with adenosine triphosphate (ATP), which in this case is free from Mg2+, but there is some Ca2+ in the vesicle. The storage of acidic transmitters appears to be with Na+ (not K+).

A second activity of the neuron does not concern ions or molecules but a variety of proteins and some enzymes. They include those in the central area, those in the synapse bulbs and those in the axons. The enzymes in the central zone catalyse tubulin synthesis for extension as the axon grows. Axon growth occurs only with repeated electrical activity of the neuron and is therefore associated with long-term memory. The proteins necessary in the synaptic bulbs for storage of the messenger molecules, transmitters, are transported along the tubulin from the central region to the bulbs. Hence the central region is responsible for transmitter synthesis, but transmitter recovery occurs at the synapses (see Glial Cells). Analysis of a nerve cell is a basic task but in the brain it is essential that, as well as general analysis, we can image where any type of neuron including its synapse is located. The study of the locations depends on: (1) direct methods for metal ions contents, including single atom microscopes, assuming that different neurons have different ion contents, (2) use of such tools as direct fluorescence or fluorescence of added dyes which may reflect contents of neurotransmitters directly as they are at high concentration in bulbous regions. Typically the presence of free or very weakly bound zinc can be detected by very high resolution electron microscopy or by the use of the dye-stuff dithizone. A very interesting example of a parallel but different direct spectroscopy analysis of vesicles of cells is that of the adrenal gland. The vesicles of the gland release transmitters in much the same fashion as the neurons do. The cells of this gland resemble neurons in that they contain adrenaline, some corticosteroids, adenosine triphosphate and a protein, chromogranin A, which is the source of certain peptide hormonal molecules such as enkephalin. Much of the content of the vesicles of the whole organ can be visualised by nuclear magnetic resonance (NMR), including all four types of messenger molecule. It is possible to use brain slices to perform similar NMR analyses.

1.4 The Enzyme Content of the Neuron

The main enzymes of the neurons are in the three groups of the normal complement of aerobic eukaryotic cells, so they can catalyse the common activities of glycolysis, the Krebs cycle and conventional syntheses. The neurons have mitochondria and the usual vesicles of the endoplasmic reticulum. In addition they must have the ability to synthesise the transmitters. In so far as the transmitters are specialised in different neurons so their enzymes must be present in the specific cell central region. The major separation of transmitters is into those that require specific oxidation, e.g. adrenaline and amidated peptides, and those that do not, e.g. glutamate. Oxidation enzymes are usually iron-containing in the cytoplasm and copper-containing in vesicles or externally. The analysis locally for copper and iron and their enzymes is therefore very useful. Some of these enzymes should be in higher concentration than in other cells. Zinc enzyme analysis, equally important, is confused by local concentrations of free zinc in vesicles. Enzymes other than those containing metal ions must be recognised by fluorescent products. We return to the distribution in the different neurons when we have described the analysis of the brain's zones.

A peculiarity of nerve cells generally but very importantly in neurons is the synthesis of the myelin sheath. Myelin is 80% lipid and 20% protein, holding the multi-layered membrane rigid. The protein somewhat resembles an outer skin of keratin and its final cross-linked state requires copper oxidases. It is very unusual for an internal cell to have such protection. Note that vitamin B12 (cobalamine is the active form of vitamin B12) is necessary to protect the synthesis of myelin.

Neurons in the brain need to grow to make new contacts so as to create long-term memory. Short-term memory may not need such growth. These nerves contain the proteins enabling extension of the axon, the cell. They must therefore have not only tubulins but actomyosin filaments and these proteins must be carried down the axons. The actomyosin proteins are also responsible for the ejection of chemical transmitters from the vesicles as their contractile function, linked to calcium stimulus, moves the vesicles to the outer membrane for discharge. The activity of the actomyosin contraction is mediated by ATP hydrolysis, which is generally of the Mg–ATP complex where Mg acts as a required unit. This activity of a kinase is dependent on calcium entry into the neuron synapse bulk. There are several metal ions of great importance in the brain and nervous system, especially sodium, potassium, magnesium, calcium, iron, copper, zinc, cobalt and manganese. The details of their distribution as free ions or in enzymes, the metallomes, in different brain zones must be a major area for future research.

1.5 Glial Cells

The glial cells (glia) which occur in the central nervous system (CNS) and in the peripheral nervous system (PNS) are much more abundant than the neurons and occupy one half of the volume of the brain. Their number in the human neocortex is about 36–39 000 000 000, and they can reproduce. For many years they were thought to have only the function of supporting the neurons physically (their name derives from the Greek glia, glue), but it is now known that besides this function they are essential to maintain and repair the neuronal system, to control the formation of the synapses and to participate in the mechanism of production of energy in the CNS, besides transporting essential ion and organic molecules to the neurons.

In effect there are five different kinds of glial cell: the astrocytes, the oligodendrocytes, the Schwann cells, the microglial cells and the satellite cells. The astrocytes (the name is derived from their star shape) are very relevant, linked to the functions of the neurons, and it can be said that they control the formation of the synapses, which they isolate, forming a kind of external barrier. The same happens near the nodes of Ranvier, near where the Na+ and K+ channels are concentrated. As mentioned above, these cells also transport ions and other substances required in an intercellular pathway by the neurons and participate in the mechanism of production of energy in the CNS, providing energetic substrates in an activity-dependent manner (pyruvate, lactate, glucose). They also regulate the level of glutamate in the synaptic space, removing K+ from these spaces, regulate the pH of the cerebrospinal fluid and connect the synaptic activity with the blood flux. Finally they protect against oxidation stress and remove toxic substances (such as ammonia and cell detritus). Note that a Mn2+ enzyme (glutamine synthetase) occurs specifically in the astrocytes and converts glutamate and ammonia to gluta mine. The astrocytes and the neurons communicate via intercellular holes or channels that allow the trafficking of ions and small molecules in the so-called "gap junctions" but they can also act by extracellular trafficking of ions and signalling molecules. In this way they help to produce a kind of network in which information circulates in the relevant areas of the brain as a chain of reactions.

Two other kinds of glial cell are the oligodendrocytes (in the CNS of evolved vertebrates) and the Schwann cells (in the PNS), both of which produce the myelin layers that coat the neuronal axons, isolating them from electronic effects and controlling the concentration of the ionic Na+/K+ channels in the nodes of Ranvier. The fourth kind of glial cell is the group of the small microglial cells that have a neuroimmunological function, responding to disease or aggression, phagocytosing cell detritus and providing anti-inflammatory responses; they have, therefore, a function of protection of other cells. The last of the five glial cells, the satellite cells, give physical support to the neurons in the PNS and help in the regulation of the external chemical environment.

(Continues...)

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Edition details

• Publisher: Royal Society of Chemistry
• Publication date: 2011
• Language: English
• ISBN 10: 1849730504
• ISBN 13: 9781849730501
• Binding: Hardcover
• Number of pages: 270
• Editor: Danilo Milardi