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METAL IONSIN LIFE SCIENCES

edited by

Astrid Sigel,�1� Helmut Sigel,�1� and Roland K. O. Sigel�2�

�1� Department of ChemistryInorganic ChemistryUniversity of BaselSpitalstrasse 51CH-4056 Basel, Switzerland

�2� Institute of Inorganic ChemistryUniversity of ZürichWinterthurerstrasse 190CH-8057 Zürich, Switzerland

VOLUME 1

Neurodegenerative Diseasesand Metal Ions


VOLUME 1



edited by

Astrid Sigel,�1� Helmut Sigel,�1� and Roland K. O. Sigel�2�

�1� Department of ChemistryInorganic ChemistryUniversity of BaselSpitalstrasse 51CH-4056 Basel, Switzerland

�2� Institute of Inorganic ChemistryUniversity of ZürichWinterthurerstrasse 190CH-8057 Zürich, Switzerland

VOLUME 1


Copyright © 2006 John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester,West Sussex PO19 8SQ, England

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Library of Congress Cataloging in Publication Data

Neurodegenerative diseases and metal ions / edited by Astrid Sigel, Helmut Sigel, and Roland K. O. Sigel.p. ; cm. — (Metal ions in life sciences ; v. 1)

Includes bibliographical references and index.ISBN-13: 978-0-470-01488-2 (cloth : alk. paper)ISBN-10: 0-470-01488-1 (cloth : alk. paper)1. Nervous system—Degeneration. 2. Nervous system—Diseases. 3. Metal ions—Health aspects.I. Sigel, Astrid. II. Sigel, Helmut. III. Sigel, Roland K. O. IV. Series.[DNLM: 1. Neurodegenerative Diseases—chemistry of. 2. Metals—adverse effects. 3. Metals—metabolism. 4. Prion Diseases—chemistry of. 5. Protein Folding. 6. Alzheimer’s Disease.7. Parkinson’s Disease. 8. Creutzfeldt-Jakob Disease. WL 359 N49438 2006]RC365.N454 2006616.8—dc22

2005032056

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

ISBN-13 978-0-470-01488-2 (HB)ISBN-10 0-470-01488-1 (HB)

Typeset in 10/12pt Times by Integra Software Services Pvt. Ltd, Pondicherry, IndiaPrinted and bound in Spain by Grafos S.A. BarcelonaThis book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least twotrees are planted for each one used for paper production.

The figure on the dustcover is part of Figure 6 of Chapter 3 by Henryk Kozlowski, Marek Luczkowski, DanielaValensin, and Gianni Valensin

www.wiley.com

Historical Development and Perspectivesof the Series

Metal Ions in Life Sciences

It is an old wisdom that metals are indispensable for life. Indeed, several ofthem, like sodium, potassium, and calcium, are easily discovered in living matter.However, the role of metals and their impact on life remained largely hiddenuntil inorganic chemistry and coordination chemistry experienced a pronouncedrevival in the 1950s. The experimental and theoretical tools created in this periodand their application to biochemical problems led to the development of the fieldor discipline now known as Bioinorganic Chemistry, Inorganic Biochemistry, ormore recently also often addressed as Biological Inorganic Chemistry.

By 1970 Bioinorganic Chemistry was established and further promoted by thebook series Metal Ions in Biological Systems founded in 1973 (edited by H.S.,who was soon joined by A.S.) and published by Marcel Dekker, Inc., New York,for more than 30 years. After this company ceased to be a family endeavor andits acquisition by another company, we decided, after having edited 44 volumesof the MIBS series (the last two together with R.K.O.S.) to launch a new andbroader-minded series to cover today’s needs in the Life Sciences. Therefore, theSigels’ new series is entitled

Metal Ions in Life Sciencesand we are happy to join forces in this new endeavor with a most experiencedpublisher in the Sciences, John Wiley & Sons, Ltd, Chichester, UK.

The development of Biological Inorganic Chemistry during the past 40 yearswas and still is driven by several factors; among these are: (i) the attemptsto reveal the interplay between metal ions and peptides, nucleotides, hormonesor vitamins, etc.; (ii) the efforts regarding the understanding of accumulation,transport, metabolism and toxicity of metal ions; (iii) the development andapplication of metal-based drugs; (iv) biomimetic syntheses with the aim tounderstand biological processes as well as to create efficient catalysts; (v) thedetermination of high-resolution structures of proteins, nucleic acids, and otherbiomolecules; (vi) the utilization of powerful spectroscopic tools allowing studiesof structures and dynamics; and (vii), more recently, the widespread use of

vi PERSPECTIVES OF THE SERIES

macromolecular engineering to create new biologically relevant structures atwill. All this and more is and will be reflected in the volumes of the series MetalIons in Life Sciences.

The importance of metal ions to the vital functions of living organisms, hence,to their health and well-being, is nowadays well accepted. However, in spiteof all the progress made, we are still only on the brink of understanding theseprocesses. Therefore, the series Metal Ions in Life Sciences will endeavor to linkcoordination chemistry and biochemistry in their widest sense. Despite the evi-dent expectation that a great deal of future outstanding discoveries will be madein the interdisciplinary areas of science, there are still ‘language’ barriers betweenthe historically separate spheres of chemistry, biology, medicine, and physics.Thus, it is one of the aims of this series to catalyze mutual ‘understanding’.

It is our hope that Metal Ions in Life Sciences proves a stimulus for newactivities in the fascinating ‘field’ of Biological Inorganic Chemistry. If so, itwill well serve its purpose and be a rewarding result for the efforts spent by theauthors.

Astrid Sigel, Helmut Sigel Roland K. O. SigelDepartment of Chemistry Institute of Inorganic ChemistryInorganic Chemistry University of ZürichUniversity of Basel CH-8057 ZürichCH-4056 Basel SwitzerlandSwitzerland

October 2005

Preface to Volume 1Neurodegenerative Diseases and Metal Ions

Over the years substantial evidence has accumulated implicating that metalions play a role in the pathophysiology and pathogenesis of neurodegenera-tive disorders. This is emphasized in Chapter 1, which sets the scene for thisvolume and provides an organizational frame for metal-related disorders, namely:(i) those caused by a defect in metal ion transport or homeostasis; (ii) thosecaused by toxicological exposure to metals; and (iii) those caused or associatedwith metalloprotein aggregation and/or misfolding.

Indeed, misfolded proteins are implicated in a rapidly growing list of debil-itating illnesses like Alzheimer’s, Parkinson’s, and Creutzfeldt–Jakob diseases.Therefore Chapter 2 deals with protein folding and misfolding; structures, ener-getics, and dynamics of transient species are considered in detail because theircharacterization is an essential step in understanding the benign and malignantpathways of protein folding.

The three chapters following these general considerations are devoted to metalion interactions, mainly of copper, with mammalian prion proteins and theirfragments, to transmissible spongiform encephalopathies (Creutzfeldt–Jakob andrelated diseases) as well as to the amyloid precursor protein (Alzheimer’s dis-ease). Chapters 6 and 7 consider in particular the role of iron in Parkinson’sand Huntington’s diseases, respectively, whereas Chapter 8 details the interrela-tion between copper–zinc superoxide dismutase and familial amyotrophic lateralsclerosis. The malfunctioning of copper transport in Wilson and Menkes dis-eases, where copper accumulates or is not absorbed, respectively, is dealt with inChapter 9. The special role of iron in neurodegenerative diseases and the chemi-cal interplay between catecholamines and metal ions are in the focus of Chapters10 and 11, respectively; in this context Parkinson’s, Alzheimer’s and Hunting-ton’s diseases are considered again, but from a different viewpoint, in addition toneurodegeneration with brain iron accumulation (NBIA, formerly Hallervorden–Spatz syndrome), neuroferritinopathy, aceruloplasminemia, Friedreich’s ataxia,and taupathies.

The disruption of the homeostasis of metal ions can have devastating effectsas is evident throughout the book. This also holds for the essential zinc; its

viii PREFACE TO VOLUME 1

metalloneurochemistry, i.e. its physiology and pathology as well as probes andsensors to detect it, are covered extensively in Chapter 12.

Next to metal ions like manganese, iron, copper, and zinc, which are essentialbut may also be toxic due to the creation of reactive oxygen species resulting inoxidative stress, there are other metal ions which are a priori neurotoxic. Amongthese is aluminum, and its role in neurodegenerative processes is reviewed inChapter 13. Cadmium, lead, and mercury are important from the viewpoint ofpublic health because they are released into the environment by human activities;their neurotoxicity is covered in Chapter 14.

The terminating Chapter 15 summarizes in a general way the medicinal chem-istry of metal-centered brain diseases and indicates other neurological disordersthat may involve metal ions like polyneuropathy, multiple sclerosis, maculardegeneration, progressive supranuclear palsy or the restless leg syndrome whichare not otherwise covered in the book because knowledge is scarce.

It is clear that there is an urgent need for developing novel drugs and classesof drugs that manipulate metal-centered neuropathology more precisely andelegantly than the presently (only partly) available chelation therapies. It is hopedthat this volume stimulates research into this direction.

Astrid SigelHelmut Sigel

Roland K. O. Sigel

Contents

HISTORICAL DEVELOPMENT AND PERSPECTIVESOF THE SERIES v

PREFACE TO VOLUME 1 viiCONTRIBUTORS TO VOLUME 1 xvTITLES OF VOLUMES 1–44 IN THE

METAL IONS IN BIOLOGICAL SYSTEMS SERIES xixCONTENTS OF VOLUMES IN THE

METAL IONS IN LIFE SCIENCES SERIES xxi

1 THE ROLE OF METAL IONS IN NEUROLOGY.AN INTRODUCTION 1Dorothea Strozyk and Ashley I. Bush

1 Introductory Remarks 12 Comments on Metal Ions in Neurology 2

Acknowledgments 5Abbreviations 5References 5

2 PROTEIN FOLDING, MISFOLDING, AND DISEASE 9Jennifer C. Lee, Judy E. Kim, Ekaterina V. Pletneva,Jasmin Faraone-Mennella, Harry B. Gray, and Jay R. Winkler

1 Introduction 102 Experimental Methods 103 The Denatured State 164 Protein Folding Dynamics 265 �-Synuclein and Parkinson’s Disease 456 Conclusions and Outlook 50

Acknowledgments 50

x CONTENTS

Abbreviations and Definitions 51References 51

3 METAL ION BINDING PROPERTIES OF PROTEINSRELATED TO NEURODEGENERATION 61Henryk Kozlowski, Marek Luczkowski,Daniela Valensin, and Gianni Valensin

1 Introduction 622 Cu2+ Interactions with Mammalian Prion Proteins and Their

Fragments 633 Interactions of Metal Ions with the Amyloid Precursor Protein

and Its Fragments 764 Concluding Remarks 82


4 METALLIC PRIONS: MINING THE CORE OFTRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES 89David R. Brown

1 Introduction 892 Historical Connections Between Copper and Transmissible

Spongiform Encephalopathies 923 Copper Binding to Prion Protein 934 Copper Coordination by Prion Protein 955 Copper Uptake and Prion Protein Internalization 976 Prion Protein as an Antioxidant 1017 Manganese Binding 1048 Transmissible Spongiform Encephalopathies and Metals 1079 Conclusions 109

Abbreviations 109References 110

5 THE ROLE OF METAL IONS IN THE AMYLOIDPRECURSOR PROTEIN AND IN ALZHEIMER’SDISEASE 115Thomas A. Bayer and Gerd Multhaup

1 Introduction 1152 Amyloid Precursor Protein and Brain Copper Homeostasis 1173 Amyloid Precursor Protein and Cu,Zn-Superoxide Dismutase-1 1194 General Conclusions 120


CONTENTS xi

6 THE ROLE OF IRON IN THE PATHOGENESIS OFPARKINSON’S DISEASE 125Manfred Gerlach, Kay L. Double, Mario E. Götz,Moussa B. H. Youdim, and Peter Riederer

1 Introduction 1262 Iron in the Etiology of Parkinson’s Disease 1283 Sources of Increased Iron in Parkinson’s Disease 1334 Consequences of Iron Overload in Parkinson’s Disease 1395 General Conclusions 141

Acknowledgments 142Abbreviations and Definitions 142References 143

7 IN VIVO ASSESSMENT OF IRON IN HUNTINGTON’SDISEASE AND OTHER AGE-RELATEDNEURODEGENERATIVE BRAIN DISEASES 151George Bartzokis, Po H. Lu, Todd A. Tishler, andSusan Perlman

1 Introduction. Puzzling Changes in Cell Numbers inHuntington’s Disease Brain 152

2 Human Brain Development and Disease Phenotypes 1543 Oligodendrocytes and Iron in Brain Development and

Degeneration 1594 Transition Metal Metabolism and Proteinopathies 1655 In Vivo Measurement of Brain Iron 1666 Novel Treatment Considerations 1687 Conclusions 168


8 COPPER-ZINC SUPEROXIDE DISMUTASE ANDFAMILIAL AMYOTROPHIC LATERAL SCLEROSIS 179Lisa J. Whitson and P. John Hart

1 Introduction 1802 Molecular Mechanisms of fALS SOD1 Pathogenesis 1813 Structural Features of Human SOD1 1874 ‘Wild-Type-like’ fALS Mutants 1905 ‘Metal Binding Region’ fALS Mutants 1916 Monomeric SOD1 and Pathogenesis 1947 Conclusions 198

Acknowledgments 199

xii CONTENTS


9 THE MALFUNCTIONING OF COPPER TRANSPORT INWILSON AND MENKES DISEASES 207Bibudhendra Sarkar

1 Introduction 2082 Clinical and Biochemical Features of Copper Transport

Disorders 2103 Genes Identified in Copper Transport Disorders 2124 Structure and Function of Copper-Transporting ATPases 2135 Treatment of Copper Transport Disorders 2176 Conclusions 221


10 IRON AND ITS ROLE IN NEURODEGENERATIVEDISEASES 227Roberta J. Ward and Robert R. Crichton

1 Introduction 2282 The Inorganic Chemistry of Iron and Its Role in Human

Biology 2293 Iron Metabolism 2304 The Role of the ‘Labile Iron Pool’ in Free Radical Production 2385 The Importance of Iron in Brain 2396 The Involvement of Iron in Neurodegenerative Diseases 2447 Experimental Approaches to Brain Iron Loading 2658 Conclusions 270


11 THE CHEMICAL INTERPLAY BETWEENCATECHOLAMINES AND METAL IONS INNEUROLOGICAL DISEASES 281Wolfgang Linert, Guy N. L. Jameson,Reginald F. Jameson, and Kurt A. Jellinger

1 General Introduction 2822 Neurodegenerative Diseases 2833 Relevant in Vitro Chemistry 2914 Iron and Parkinson’s Disease 2985 Relevant Manganese Chemistry 306

CONTENTS xiii

6 Manganese and Manganosis 3067 Other Metal Ions and Catecholamines 3088 Summary of the Effect of Metal Ions on Autoxidation of

Dopamine 3119 Conclusions 312


12 ZINC METALLONEUROCHEMISTRY: PHYSIOLOGY,PATHOLOGY, AND PROBES 321Christopher J. Chang and Stephen J. Lippard

1 Introduction 3222 Zinc in the Brain 3233 Zinc Sensing for Neuroscience Applications 3284 Biomolecule Fluorescent Probes for Zinc 3295 Small-Molecule Fluorescent Probes for Zinc 3396 Concluding Remarks and Future Directions 359


13 THE ROLE OF ALUMINUM IN NEUROTOXICAND NEURODEGENERATIVE PROCESSES 371Tamás Kiss, Krisztina Gajda-Schrantz, and Paolo F. Zatta

1 Introduction 3722 Chemical Forms of Aluminum in Biological Systems 3743 Aluminum Loading in Humans 3774 Toxicology of Aluminum in Animals and Humans 3805 Aluminum and Alzheimer’s Disease 3846 General Conclusions 387


14 NEUROTOXICITY OF CADMIUM, LEAD, ANDMERCURY 395Hana R. Pohl, Henry G. Abadin, and John F. Risher

1 Introduction 3962 Cadmium 3973 Lead 4004 Mercury 4095 Conclusions 415

xiv CONTENTS


15 NEURODEGENERATIVE DISEASES AND METALIONS. A CONCLUDING OVERVIEW 427Dorothea Strozyk and Ashley I. Bush

1 Introduction 4282 The Medicinal Chemistry of Metal-centered Brain Disorders 4283 Other Neurological Disorders that May Involve Metals 4304 Conclusion and Outlook 432


SUBJECT INDEX 437

Contributors

Numbers in parentheses indicate the pages on which the authors’ contribu-tions begin.

Henry G. Abadin Agency for Toxic Substances and Disease Registry(ATSDR), US Department of Health and Human Services, Division of Toxicol-ogy, Mailstop E-29, 1600 Clifton Road, Atlanta, GA 30333, USA (395)

George Bartzokis (1) Department of Neurology, Alzheimer’s Disease Cen-ter, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza,Los Angeles, CA 90095-1769, USA, <[email protected]>, (2) Laboratory ofNeuroimaging, Department of Neurology, Division of Brain Mapping, UCLA,Los Angeles, CA 90095, USA, (3) Greater Los Angeles VA Healthcare System,Department of Psychiatry, West Los Angeles, CA 90073, USA, and (4) Depart-ment of Psychiatry, Charles R. Drew University of Medicine and Science, LosAngeles, CA 90043, USA (151)

Thomas A. Bayer Universität des Saarlandes, Klinik für Psychiatrie, Abteilungfür Neurobiologie, D-66421 Homburg/Saar, Germany,<[email protected]> (115)

David R. Brown Department of Biology and Biochemistry, University of Bath,Bath BA2 7AY, UK, <[email protected]> (89)

Ashley I. Bush (1) Laboratory for Oxidation Biology, Genetics and AgingResearch Unit, Harvard Medical School, Massachusetts General Hospital,Bldg 114, 16th Street, Charlestown, MA 02129, USA, <[email protected]>, and (2) Oxidation Disorders Laboratory, Mental Health ResearchInstitute of Victoria, and Department of Pathology, The University of Melbourne,155 Oak Street, Parkville, Victoria 3052, Australia (1, 427)

Christopher J. Chang Department of Chemistry, Massachusetts Institute ofTechnology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA (321)

xvi CONTRIBUTORS

Robert R. Crichton Unité de Biochimie, Université Catholique deLouvain, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium,<[email protected]> (227)

Kay Double Prince of Wales Medical Research Institute, Barker St., Randwick,Sydney, NSW, 2031, Australia, <[email protected]> (125)

Jasmin Faraone-Mennella Beckman Institute, California Institute of Technol-ogy, Pasadena, CA 91125, USA (9)

Krisztina Gajda-Schrantz Department of Inorganic and Analytical Chem-istry, Bioinorganic Chemistry Research Group of the Hungarian Academy ofSciences, University of Szeged, P.O. Box 440, H-6701 Szeged, Hungary (371)

Manfred Gerlach Department of Child and Adolescence Psychiatry andPsychotherapy, Clinical Neurochemistry, University of Würzburg, Füchslein-strasse 15, D-97080 Würzburg, Germany,<[email protected]> (125)

Mario E. Götz Department of Pharmacology, Universitätsklinikum Kiel, Hos-pitalstrasse 4, D-24105 Kiel, Germany, <[email protected]>

(125)

Harry B. Gray Beckman Institute, California Institute of Technology,Pasadena, CA 91125, USA, <[email protected]> (9)

P. John Hart Department of Biochemistry and the X-Ray CrystallographyCore Laboratory, The University of Texas Health Science Center, 7703 FloydCurl Drive, San Antonio, TX 78229-3900, USA,<[email protected]. edu> (179)

Guy N. L. Jameson Institute of Applied Synthetic Chemistry, Vienna Uni-versity of Technology, Getreidemarkt 9/163-AC, A-1060 Vienna, Austria,<[email protected]> (281)

Reginald F. Jameson Emeritus Professor, University of Dundee, Scotland,UK, <[email protected]> (281)

Kurt Jellinger Institute of Clinical Neurobiology, Kenyongasse 18, A-1070Vienna, Austria, <[email protected]> (281)

Judy E. Kim Beckman Institute, California Institute of Technology, Pasadena,CA 91125, USA (9)

CONTRIBUTORS xvii

Tamás Kiss Department of Inorganic and Analytical Chemistry, BioinorganicChemistry Research Group of the Hungarian Academy of Sciences, Universityof Szeged, P.O. Box 440, H-6701 Szeged, Hungary,<[email protected]> (371)

HenrykKozlowski FacultyofChemistry,UniversityofWroclaw,F. Joliot-Curie14, 50-383 Wroclaw, Poland, <[email protected]> (61)

Jennifer C. Lee Beckman Institute, California Institute of Technology,Pasadena, CA 91125, USA, <[email protected]> (9)

Wolfgang Linert Institute of Applied Synthetic Chemistry, Vienna Uni-versity of Technology, Getreidemarkt 9/163-AC, A-1060 Vienna, Austria,<[email protected]> (281)

Stephen J. Lippard Department of Chemistry, Massachusetts Instituteof Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA,<[email protected]> (321)

Po H. Lu (1) Department of Neurology, Alzheimer’s Disease Center, TheDavid Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles,CA 90095-1769, USA, and (2) Greater Los Angeles VA Healthcare System,Department of Psychiatry, West Los Angeles, CA 90073, USA (151)

Marek Luczkowski Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland, <[email protected]> (61)

Gerd Multhaup Institut für Chemie/Biochemie, Freie Universität Berlin,Thielallee 63, D-14195 Berlin, Germany, <[email protected]>(115)

Susan Perlman Department of Neurology, Alzheimer’s Disease Center, theDavid Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles,CA 90095-1769, USA (151)

Ekaterina V. Pletneva Beckman Institute, California Institute of Technology,Pasadena, CA 91125, USA (9)

Hana R. Pohl Agency for Toxic Substances and Disease Registry (ATSDR),US Department of Health and Human Services, Division of Toxicology, MailstopF-32, 1600 Clifton Road, Atlanta, GA 30333, USA, <[email protected]> (395)

Peter Riederer Department of Psychiatry and Psychotherapy, Clinical Neu-rochemistry, National Parkinson Foundation Centers of Excellence for Neu-rodegenerative Diseases Research, University of Würzburg, Füchsleinstrasse 15,D-97080 Würzburg, Germany, <[email protected]> (125)

xviii CONTRIBUTORS

John F. Risher Agency for Toxic Substances and Disease Registry (ATSDR),US Department of Health and Human Services, Division of Toxicology, MailstopE-29, 1600 Clifton Road, Atlanta, GA 30333, USA (395)

Bibudhendra Sarkar (1) The Research Institute, The Hospital for SickChildren, Toronto, and (2) The Department of Biochemistry, Universityof Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada,<[email protected]> (207)

Dorothea Strozyk Department of Neurology, Albert Einstein College ofMedicine, Kennedy Center, Suite 220, Pelham Parkway South, Bronx, NY 10461,USA, <[email protected]> (1, 427)

Todd A. Tishler (1) Department of Neurology, Alzheimer’s Disease Center,The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, LosAngeles, CA 90095-1769, USA, (2) Greater Los Angeles VA Healthcare System,Department of Psychiatry, West Los Angeles, CA 90073, and (3) NeuroscienceInterdepartmental Graduate Program, The David Geffen School of Medicine atUCLA, Los Angeles, CA 90095, USA (151)

Daniela Valensin Department of Chemistry, University of Siena, Via AldoMoro, I-53100 Siena, Italy (61)

Gianni Valensin Department of Chemistry, University of Siena, Via AldoMoro, I-53100 Siena, Italy, <[email protected]> (61)

Roberta J. Ward Unité de Biochimie, Université Catholique de Louvain, PlaceLouis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium, <[email protected]>(227)

Lisa J. Whitson Department of Biochemistry and the X-Ray Crys-tallography Core Laboratory, The University of Texas Health ScienceCenter, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA,<[email protected]> (179)

Jay R. Winkler Beckman Institute, California Institute of Technology,Pasadena, CA 91125, USA, <[email protected]> (9)

Moussa B. H. Youdim Eve Topf and National Parkinson Foundation Centersof Excellence for Neurodegenerative Diseases Research, and Department ofPharmacology, Technion-Faculty of Medicine, Efron St., PO Box 9697, Haifa31096, Israel, <[email protected]> (125)

Paolo F. Zatta CNR Institute for Biomedical Technologies, MetalloproteinsUnit, Department of Biology, University of Padova, Viale G. Colombo 3, I-35121Padova, Italy, <[email protected]> (371)

Titles of Volumes 1–44 in theMetal Ions in Biological Systems Series

edited by the SIGELsand published by Dekker/Taylor & Francis

Volume 1: Simple ComplexesVolume 2: Mixed-Ligand ComplexesVolume 3: High Molecular ComplexesVolume 4: Metal Ions as ProbesVolume 5: Reactivity of Coordination CompoundsVolume 6: Biological Action of Metal IonsVolume 7: Iron in Model and Natural CompoundsVolume 8: Nucleotides and Derivatives: Their Ligating AmbivalencyVolume 9: Amino Acids and Derivatives as Ambivalent Ligands

Volume 10: Carcinogenicity and Metal IonsVolume 11: Metal Complexes as Anticancer AgentsVolume 12: Properties of CopperVolume 13: Copper ProteinsVolume 14: Inorganic Drugs in Deficiency and DiseaseVolume 15: Zinc and Its Role in Biology and NutritionVolume 16: Methods Involving Metal Ions and Complexes in

Clinical ChemistryVolume 17: Calcium and Its Role in BiologyVolume 18: Circulation of Metals in the EnvironmentVolume 19: Antibiotics and Their ComplexesVolume 20: Concepts on Metal Ion ToxicityVolume 21: Applications of Nuclear Magnetic Resonance to

Paramagnetic SpeciesVolume 22: ENDOR, EPR, and Electron Spin Echo for Probing

Coordination SpheresVolume 23: Nickel and Its Role in BiologyVolume 24: Aluminum and Its Role in BiologyVolume 25: Interrelations Among Metal Ions, Enzymes, and

Gene ExpressionVolume 26: Compendium on Magnesium and Its Role in Biology,

Nutrition, and Physiology

xx VOLUMES IN THE MIBS SERIES

Volume 27: Electron Transfer Reactions in MetalloproteinsVolume 28: Degradation of Environmental Pollutants by Microorganisms

and Their MetalloenzymesVolume 29: Biological Properties of Metal Alkyl DerivativesVolume 30: Metalloenzymes Involving Amino Acid-Residue and

Related RadicalsVolume 31: Vanadium and Its Role for LifeVolume 32: Interactions of Metal Ions with Nucleotides, Nucleic Acids,

and Their ConstituentsVolume 33: Probing Nucleic Acids by Metal Ion Complexes of

Small MoleculesVolume 34: Mercury and Its Effects on Environment and BiologyVolume 35: Iron Transport and Storage in Microorganisms, Plants,

and AnimalsVolume 36: Interrelations Between Free Radicals and Metal Ions

in Life ProcessesVolume 37: Manganese and its Role in Biological ProcessesVolume 38: Probing of Proteins by Metal Ions and Their

Low-Molecular-Weight ComplexesVolume 39: Molybdenum and Tungsten.

Their Roles in Biological ProcessesVolume 40: The Lanthanides and Their Interrelations with BiosystemsVolume 41: Metal Ions and Their Complexes in MedicationVolume 42: Metal Complexes in Tumor Diagnosis and as Anticancer

AgentsVolume 43: Biogeochemical Cycles of ElementsVolume 44: Biogeochemistry, Availability, and Transport of Metals

in the Environment

Contents of Volumes in theMetal Ions in Life Sciences Series

edited by the SIGELsand published by John Wiley & Sons, Ltd, Chichester, UK

<http://www.wiley.com>

Volume 1: Neurodegenerative Diseases and Metal Ions(this book)

Volume 2: Nickel and Its Surprising Impact in Nature(tentative contents)

1. The Biogeochemistry of Nickel and Its Release into the EnvironmentTiina M. Nieminen, Liisa Ukonmaanaho, Nicole Rausch,and William Shotyk

2. Nickel in the Environment and Its Role in Plant MetabolismHendrik Küpper and Peter M. H. Kroneck

3. Nickel Ion Complexes of Amino Acids and PeptidesTeresa Kowalik-Jankowska, Henryk Kozlowski, Etelka Farkas,and Imre Sóvágó

4. Complex Formation of Nickel(II) with Nucleobases, Phosphates,Nucleotides, and Nucleic AcidsRoland K. O. Sigel and Helmut Sigel

5. Synthetic Models for the Active Sites of Nickel-containing EnzymesFranc Meyer

6. Urease. Recent Insights in the Role of NickelStefano Ciurli

7. Nickel-Iron HydrogenasesWolfgang Lubitz

8. Methyl-Coenzyme M Reductase and Its Nickel Corphin Cofactor F430

Rudolf K. Thauer9. Acetyl-Coenzyme A Synthases and Nickel-containing Carbon Monoxide

DehydrogenasesPaul A. Lindahl and David E. Graham

10. Nickel Superoxide DismutasePeter A. Bryngelson and Michael J. Maroney

11. Biochemistry of the Nickel-dependent Glyoxalase I EnzymesNicole Sukdeo, Elizabeth Daub, and John F. Honek

xxii CONTENTS OF FUTURE MILS VOLUMES

12. Nickel in Acireductone DioxygenaseThomas C. Pochapsky

13. The Nickel-Regulated Peptidyl-Prolyl cis/trans Isomerase SlyDFrank Erdmann and Gunter Fischer

14. Chaperones of Nickel MetabolismSoledad Quiroz, Jong K. Kim, Scott Mulrooney, and Robert P. Hausinger

15. The Role of Nickel in Environmental Adaptation of the Gastric PathogenHelicobacter pyloriFlorian D. Ernst, Arnoud H. M. van Vliet, Manfred Kist,Johannes G. Kusters, and Stefan Bereswill

16. The Effect of Nickel on Gene ExpressionKonstantin Salnikow and Kazimierz Kasprzak

17. Nickel Toxicity and CarcinogenesisKazimierz Kasprzak and Konstantin SalnikowSubject Index

Volume 3: The Ubiquitous Roles of Cytochrome P450 Proteins(tentative contents)

1. Diversity and Similarity of P450 Systems. An IntroductionStephen G. Sligar and Mary A. Schuler

2. Structural and Functional Mimics of Cytochromes P450Wolf-D. Woggon

3. Structures of P450 Proteins and Their Molecular PhylogenyThomas L. Poulos

4. Aquatic P450 SpeciesMark J. Snyder

5. The Electrochemistry of Cytochrome P450 SystemsAlan M. Bond, Barry D. Fleming, and Lisandra L. Martin

6. Electron Transfer Reactions of Cytochrome P450Stephen M. Contakes, Yen Hoang Le Nguyen, Andrew K. Udit, and HarryB. Gray

7. Cytochromes P450. Mechanistic ConsiderationsMichael T. Green

8. Leakage in Cytochrome P450 Reactions in Relation to Protein StructuralPropertiesChristiane Jung

9. Cytochromes P450. Structural Basis for Binding and CatalysisIlme Schlichting

10. Beyond Heme-Thiolate Interactions. Roles of the Secondary CoordinationSphere in P450 SystemsYi Lu

11. Interactions of Cytochrome P450 with Nitrogen Monoxide and RelatedLigandsAndrew W. Munro

CONTENTS OF FUTURE MILS VOLUMES xxiii

12. Cytochrome P450-Catalyzed Hydroxylations and EpoxidationsRoshan Perera, S. Jin, Masanori Sono, and John H. Dawson

13. Cytochromes P450 and Steroid HormonesMichael R. Waterman and Rita Bernhard

14. Carbon–Carbon Bond Cleavage by P450 SystemsJames J. De Voss and Max J. Cryle

15. Drug Metabolism as Catalyzed by Cytochrome P450 SystemsF. Peter Guengerich

16. Chemical Defence and Exploitation: Biotransformation of Xenobiotics byCytochrome P450Elizabeth M. J. Gillam

17. Design and Engineering of P450 SystemsStephen Bell, Nicola Hoskins, Christopher Whitehouse, and Luet L. WongSubject Index

Comments and suggestions with regard to contents, topics, and the like for futurevolumes of the series are welcome.

Met. Ions Life Sci. 1, 1–7 (2006)

1

The Role of Metal Ions in Neurology.An Introduction

Dorothea Strozyk1 and Ashley I. Bush2�3

1Department of Neurology, Albert Einstein College of Medicine, Kennedy Center, Suite 220,Pelham Parkway South, Bronx, NY 10461, USA

<[email protected]>

2Laboratory for Oxidation Biology, Genetics and Aging Research Unit,Harvard Medical School, Massachusetts General Hospital,Building 114, 16th Street, Charlestown, MA 02129, USA

<[email protected]>

3Oxidation Disorders Laboratory, Mental Health Research Institute of Victoria,and Department of Pathology, The University of Melbourne,

155 Oak Street, Parkville, Victoria 3052, Australia

1 INTRODUCTORY REMARKS 12 COMMENTS ON METAL IONS IN NEUROLOGY 2

ACKNOWLEDGMENTS 5ABBREVIATIONS 5REFERENCES 5

1 INTRODUCTORY REMARKS

Substantial evidence has accumulated implicating metals in the pathophysiologyandpathogenesisofneurodegenerativedisorders suchasAlzheimer’sdisease (AD),Parkinson’s disease and amyotrophic lateral sclerosis. Interactions between redox-active metal ions and proteins can lead to damage of critical biological systemsand initiate a cascade of events leading to oxidative damage, neurodegeneration

Metal Ions in Life Sciences, Volume 1 Edited by Astrid Sigel, Helmut Sigel and Roland K. O. Sigel© 2006 John Wiley & Sons, Ltd

2 STROZYK and BUSH

and cell death. Here we address the recent advances in understanding the molec-ular mechanisms of metal ion activity in the brain and nervous system, and welist neurological diseases that have been associated with metal ions and proposea conceptual model for organizing neurological disorders where metal ions areimplicated.

2 COMMENTS ON METAL IONS IN NEUROLOGY

The relevance of biological metals to neuroscience has burgeoned in this firstdecade of the 21st century. In 2000 we noted that the neurobiology of the heaviermetal ions did not arouse much interest since they were not notably linked tomajor disease syndromes [1]. As we foresaw, this outlook currently is changingrapidly, with a growing number of excellent publications pointing the way to aseminal relationship between Fe, Cu, Mn, and Zn in the generation (or defence)of oxygen and protein radicals that mediate the major neurological diseases.

However, there continues to be notable resistance among the mainstreamof the neuroscience community to the appreciation of the importance of thisemerging literature. This is probably because neuroscientists are not usuallyexposed to the basics of metallochemistry and oxidation chemistry duringtraining, which emphasizes the value of cellular and molecular approaches, andbecause biochemical training has traditionally deemphasized the role of metalions in metabolic reactions, which is why they have been pejoratively termed‘trace metals’. This is a misnomer since the concentrations of Fe, Zn and Cu inthe gray matter are in the same order of magnitude as Mg (0.1–0.5 mM) [2].

The brain utilizes metal ions for myriad biochemical reactions, and cor-tical neurons release ionically exchangeable copper [3] and zinc [4] duringdepolarization and neurotransmission. Abnormalities of metal ion biochemistryin neural tissue arise by two basic mechanisms: (i) protein aggregation medi-ated by metal ions, e.g., zinc induction of Alzheimer’s disease �-amyloid �A��deposits [5]; and (ii) oxidative reactions catalyzed by redox-active metals.

Redox-active metals (Cu, Fe, Mn) can generate radicals and reactive oxygen(ROS) and nitrogen species, by inappropriately accepting or donating electrons(a redox-active metal refers to a metal ion that can change its valence state underbiological conditions). However, metal ions like Cd(II), Hg(II), Al(III), and Pb(II)can also affect redox reactions in indirect ways. Redox-active metal ions like Cu,Fe, and Mn are needed for essential biochemical activities and antioxidant defencessuch as cytochrome c oxidase and superoxide dismutase 1 (Cu), hemoglobin andcis-aconitase (Fe), and superoxide dismutase 2 (Mn). Because of the problem ofinappropriate electron transfer from these metal ions, metalloproteins have highlystructured active sites that are small and substrate-specific. Also, all cells havestringent chaperone mechanisms in place to prevent side reactions of these metalswith incorrect substrates. This is probably why there is no free Cu or Fe in the cell,rather these metals are always chaperoned [6]. The blood–brain barrier is relatively


METAL IONS IN NEUROLOGY. AN INTRODUCTION 3

impermeable to passive fluctuation of the major metal ions Zn, Cu, and Fe (e.g., dueto prandial or environmental status). Therefore, the etiology of neurodegenerativedisease is more likely to be due to homeostatic failure of the endogenous contentof metals in the brain than due to environmental or nutritional exposure. However,this important issue has not really been settled with empirical evidence.

The brain has the highest metabolic rate of any tissue and has an obligaterequirement for aerobic metabolism. This, combined with endogenously highconcentrations of Cu and Fe, increase the vulnerability of brain gray matter toradical attack when metal chaperoning is less than perfect. Redox-active metalsbecome available for ROS and radical generation when they either escape theirchaperones (usually because the concentration of metal is too high to be com-pletely chaperoned), or because of an accumulation of a damaged metalloproteinthat inappropriately permits reaction of the metal with oxygen (Figure 1). Some

O2 O2

Mx–1 Mx

H2O2e–

OH.

Mx–1

Lipid peroxidationProtein oxidationProtein aggregationDNA/RNA adducts

Metalloproteinaggregates

Reducingagents

–

Figure 1. Reactive oxygen species generation by redox-active metals as the basis for‘oxidation disorders’. The vast majority of biochemical radicals and ROS arise from theredox chemistry of metals. Dissolved molecular oxygen �O2� is liable to react with redoxactive metals (Mx, representing Cu or Fe ions most commonly, but also occasionallyCd, Hg, and Pb which may indirectly participate in redox reactions). Cu and Fe ions intheir reduced state �Mx−1� will reduce O2 to superoxide O−

2 , which is then dismutated ordisproportionated to H2O2, which is freely permeable across lipid membranes, and, if notcleared by scavenging mechanisms (e.g., catalase or glutathione peroxidase) can gener-ate the highly reactive hydroxyl radical �OH•� upon reaction with encountered reducedmetal �Mx−1�. The hydroxyl radical reacts within nanometers and generates a variety ofoxidative damage adducts that typify the chemical damage observed in neurodegenera-tive disorders like Alzheimer’s disease and Parkinson’s disease. In these conditions, thereduced metal ions (especially Cu+) are generated by the aggregating protein (e.g., A� inAlzheimer’s disease). Biological reducing agents (e.g., cholesterol) are recruited by theA� � Cu complex, fostering the catalytic generation of H2O2 [32]. The catalytic generationof H2O2 in this manner has been considered to be possible in other neurodegenerativediseases characterized by protein aggregation such as Creutzfeldt–Jakob disease (PrP),Parkinson’s disease (�-synuclein), and amyotrophic lateral sclerosis (CuZnSOD).


4 STROZYK and BUSH

metal ions like Hg(II), Cd(II), Pb(II), and Al(III) do not subserve physiologicalpurposes, and accumulate in neurons where the high metabolic rate and oxygenrequirement of the tissue make toxic exposure to these metals likely to exhibit aneurological phenotype.

We propose an organizational scheme for neurological disease where metalions are implicated (Table 1). In the last five years the category of neurological

Table 1. Organizational framework for the involvement of metals in neurological dis-ease. The disorders listed are confined to instances where there is a prominent or primaryneurological phenotype, and does not address secondary syndromes (e.g., due to mineraldeficiencies).

Metal Phenotype Protein References

1. Genetic disorders of metal metabolismCopper Wilson’s disease Cu7B ATPase [9], Chapter 9Copper Menkes’ disease Cu7A ATPase [10,11], Chapter 9Iron Neurodegeneration

with brain ironaccumulation(NBIA, formerlyHallervorden–Spatzdisease)

Pantothenate kinase 2 [12,13], Chapter 10

Iron Friedreich’s ataxia Frataxin [14], Chapter 10Iron, Copper Aceruloplasminemia Ceruloplasmin [15], Chapter 10

2. Toxicological exposure to metalAluminum ?Alzheimer’s disease ? [16], Chapter 13Cadmium Various ? Glutathione Chapter 14Lead Various ? Glutathione Chapter 14Mercury Various ? Glutathione Chapter 14Manganese Parkinsonism Cis-aconitase [17], Chapters 6, 11

3. Protein aggregation disorders involving metals in pathogenesisZinc, copper Alzheimer’s disease �-amyloid [5,18],

Chapters 5, 11Iron, copper Parkinson’s disease �-synuclein [19–22],

Chapters 6, 11Copper, zinc Amyotrophic

lateral sclerosisSuperoxidedismutase 1

[23–25],Chapters 8, 11

Copper, zinc,manganese

Transmissiblespongiformencephalopathy

PrP [26–28],Chapters 3, 4

Zinc Drusen, Sorsby’sfundus dystrophy

Tissue inhibitor ofmatrixmetalloproteinase-3(TIMP3)

[29,30]

Copper Cataracts �-B-crystallin [31]


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