Neurodegeneration: Metallostasis and Proteostasis (RSC Drug Discovery, Band 7) - Hardcover

Hardcover

ISBN 10: 1849730504 ISBN 13: 9781849730501

Verlag: Royal Society of Chemistry, 2011

Inhaltsangabe

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.

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Über die Autorinnen und Autoren

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.

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.

Von der hinteren Coverseite

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.

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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...

Details zur Ausgabe

• Verlag: Royal Society of Chemistry
• Erscheinungsdatum: 2011
• Sprache: Englisch
• ISBN 10: 1849730504
• ISBN 13: 9781849730501
• Einband: Gebundene Ausgabe
• Auflage: 1
• Anzahl der Seiten: 270
• Herausgeber: Milardi Danilo, Rizzarelli Enrico
• Kontakt zum Hersteller: Nicht verfügbar
• Verantwortliche Person: Buchpark GmbH; gpsr@buchpark.de; ; Krügerweg 1; Trebbin; Brandenburg; 14959; Deutschland