Pathogenesis of Neurodegenerative Disorders Pathogenesis of Neurodegenerative Disorders Edited by Mark P. Mattson Edited by Mark P. Mattson HUMANA PRESS HUMANA PRESS Pathogenesis of Neurodegenerative Disorders Contemporary Neuroscience Pathogenesis of Neurodegenerative Disorders, edited by Mark P. Mattson, 2001 Neurobiology of Spinal Cord Injury, edited by Robert G. Kalb and Stephen M. Strittmatter, 2000 Cerebral Signal Transduction: From First to Fourth Messengers, edited by Maarten E. A. Reith, 2000 Central Nervous System Diseases: Innovative Animal Models from Lab to Clinic, edited by Dwaine F. Emerich, Reginald L. Dean, III, and Paul R. Sanberg, 2000 Mitochondrial Inhibitors and Neurodegen- erative Disorders, edited by Paul R. Sanberg, Hitoo Nishino, and Cesario V. Borlongan, 2000 Cerebral Ischemia: Molecular and Cellular Pathophysiology, edited by Wolfgang Walz, 1999 Cell Transplantation for Neurological Disorders, edited by Thomas B. 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Plasticity and Regeneration, edited by Antonia Ve rnadakis and Betty I. Roots, 1995 Neuron–Glia Interrelations During Phylogeny: I. Phylogeny and Ontogeny of Glial Cells, edited by Antonia Vernadakis and Betty I. Roots, 1995 The Biology of Neuropeptide Y and Related Peptides, edited by William F. Colmers and Claes Wahlestedt, 1993 Psychoactive Drugs: Tolerance and Sensiti- zation, edited by A. J. Goudie and M. W. Emmett-Oglesby, 1989 Experimental Psychopharmacology, edited by Andrew J. Greenshaw and Colin T. Dourish, 1987 Developmental Neurobiology of the Auto- nomic Nervous System, edited by Phyllis M. Gootman, 1986 The Auditory Midbrain, edited by Lindsay Aitkin, 1985 Neurobiology of the Trace Elements, edited by Ivor E. Dreosti and Richard M. Smith: Vol. 1: Trace Element Neurobiology and Deficiencies, 1983; Vol. 2: Neurotoxicology and Neuropharmacology, 1983 Pathogenesis of Neurodegenerative Disorders Edited by Mark P. Mattson National Institute on Aging, Baltimore, MD Humana Press Totowa, New Jersey © 2001 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All authored papers, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256-1699; Fax: 973-256-8341; E-mail: humana@humanapr.com, or visit our Website: http://humanapress.com This publication is printed on acid-free paper. ' ANSI Z39.48-1984 (American Standards Institute) Permanence of Paper for Printed Library Materials. Cover illustration: The cover shows a silver-strained tissue section from the hippocampus of a patient with Alzheimer’s disease. The flame-shaped cell bodies of degenerating neurons (neurofibrillary tangles) and their neurites associated with amyloid deposits are stained black. The inset shows an electron micrograph of a cultured embryonic human cerebral cortical neuron that had been exposed to conditions that disrupt cellular calcium homeostasis and trigger a form of programmed cell death called apoptosis. Micrographs provided by M. P. Mattson. Cover design by Patricia F. Cleary. Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $10.00 per copy, plus US $00.25 per page, is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [0-89603-838-6/01 $10.00 + $00.25]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 Library of Congress Cataloging-in-Publication Data The pathogenesis of neurodegenerative disorders / edited by Mark P. Mattson. p. c.m.––(Contemporary neuroscience) Includes bibliographical references and index. ISBN 0-89603-838-6 (alk. paper) 1. Nervous system––Degeneration––Pathogenesis. I. Mattson, Mark Paul. II. Series. RC365 .P385 2001 616.8'0407––dc21 00-063355 As the average life expectancy of many populations throughout the world increases, so to does the incidence of such age-related neurodegenerative disorders as Alzheimer's, Parkinson's, and Huntington's diseases. Rapid advances in our understanding of the molecular genetics and environmental factors that either cause or increase risk for age-related neurodegenerative disor- ders have been made in the past decade. The ability to evaluate, at the cellular and molecular level, abnormalities in postmortem brain tissue from patients, when taken together with the development of valuable animal and cell-culture models of neurodegenerative disorders has allowed the identification of sequences of events within neurons that result in their demise in specific neurodegenerative disorders. Though the genetic and environmental factors that pro- mote neurodegeneration may differ among disorders, shared biochemical cascades that will ultimately lead to the death of neurons have been identified. These cascades involve oxyradical production, aberrant regulation of cellular ion homeostasis and activation of a stereotyped sequence of events involving mitochondrial dysfunction and activa- tion of specific proteases. Pathogenesis of Neurodegenerative Disorders provides a timely compilation of articles that encompasses fundamental mechanisms involved in neurodegenerative disorders. In addition, mechanisms that may prevent age-related neurodegenerative disorders are presented. Each chapter is written by an expert in the particular neurodegenerative disorder or mechanism or neuronal death discussed. Chapters that consider the role of oxidative stress as a central feature of all neurodegenerative disorders and the funda- mental mechanisms of neuronal apoptosis and excitotoxicity, two forms of cell death central to many different neurodegenerative disorders, open this volume. Subsequent chapters focus on specific neurodegenerative disorders. Each chapter presents infor- mation on genetic and environmental factors that may contribute to these disorders and cell death cascades involved in these disorders are detailed. Chapters focus on Parkinson’s disease, trinucleotide repeat disorders (including Huntington’s disease), Alzheimer’s disease and Down’s syndrome (two disorders that appear to involve shared mechanisms), amyotrophic lateral sclerosis, ischemic stroke, spinal cord injury, and Duchenne muscular dystrophy. Pathogenesis of Neurodegenerative Disorders will provide a valuable working ref- erence for graduate students and postdocs beginning their careers in this field. In addition, because each chapter presents the most up-to-date specific information in the field, this book is valuable for senior scientists in allowing them to integrate information on cellular and molecular mechanisms across the wide field of neurodegenerative disorders. Mark P. Mattson Preface v vi Preface Preface v Contributors ix 1Mechanisms of Neuronal Apoptosis and Excitotoxicity Mark P. Mattson 1 2Oxidative Alterations in Neurodegenerative Diseases William R. Markesbery, Thomas J. Montine, and Mark A. Lovell 21 3 Parkinson’s Disease M. T. Silva and A. H. V. Schapira 53 4 Scope of Trinucleotide Repeat Disorders Shoji Tsuji 81 5Mechanisms of Neuronal Death in Huntington’s Disease Vassilis E. Koliatsos, Carlos Portera-Cailliau, Gabrielle Schilling, David B. Borchelt, Mark W. Becher, and Christopher A. Ross 93 6Cellular and Molecular Mechanisms Underlying Synaptic Degeneration and Neuronal Death in Alzheimer’s Disease Mark P. Mattson, Ward A. Pedersen, and Carsten Culmsee 113 7Oxidative Stress in Down Syndrome: A Paradigm for the Pathogenesis of Neurodegenerative Disorders Rocco C. Iannello and Ismail Kola 139 8 The Pathogenesis of Amyotrophic Lateral Sclerosis Stanley H. Appel and R. Glenn Smith 149 9 Experimental Genetics as a Tool for Understanding Pathogenesis of ALS Philip C. Wong, Donald L. Price, and Jamuna Subramaniam 173 10 Pathogenesis of Ischemic Stroke Mark P. Mattson and Carsten Culmsee 191 11 Spinal-Cord Injury Isabel Klusman and Martin E. Schwab 217 12 The Pathogenesis of Duchenne Muscular Dystrophy Edward A. Burton and Kay E. Davies 239 Index 285 Contents vii Contributors STANLEY H. APPEL, Department of Neurology, Baylor College of Medicine, Houston, TX MARK W. BECHER, Department of Pathology (Neuropathology Division), University of New Mexico Health Sciences Center, Albuquerque, NM DAVID B. BORCHELT, Department of Pathology (Neuropathology Division and Neuroscience), Johns Hopkins University School of Medicine, Baltimore, MD EDWARD A. BURTON, Department of Human Anatomy and Genetics, University of Oxford, Oxford, England CARSTEN CULMSEE, Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD KAY E. DAVIES, Department of Human Anatomy and Genetics, University of Oxford, Oxford, England ROCCO C. IANNELLO, Centre for Functional Genomics and Human Disease, Monash Medical Centre, Clayton, Australia ISMAIL KOLA, Centre for Functional Genomics and Human Disease, Monash Medical Centre, Clayton, Australia ISABEL KLUSMAN, Brain Research Institute, University of Zurich, and Swiss Federal Institute of Technology, Zurich, Switzerland VASSILIS E. KOLIATSOS, Departments of Pathology (Neuropathology Division), Neurology, Neuroscience, and Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD MARK A. LOVELL, Sanders-Brown Center on Aging and Alzheimer's Disease Research Center and Department of Chemistry, University of Kentucky, Lexington, KY WILLIAM R. MARKESBERY, Sanders-Brown Center on Aging and Alzheimer's Disease Research Center, University of Kentucky, Lexington, KY, and Departments of Pathology and Neurology, Vanderbilt University, Nashville, TN MARK P. MATTSON, Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD THOMAS J. MONTINE, Department of Pathology, Vanderbilt University, Nashville, TN W ARD A. PEDERSEN, Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD CARLOS PORTERA-CAILLIAU, The Neuroscience Institute, Good Samaritan Hospital, Los Angeles, CA DONALD L. PRICE, Departments of Pathology, Neurology, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD CHRISTOPHER A. ROSS, Departments of Neuroscience, and Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD ix [...]... throughout the lifetime of an individual However, many people will not complete their lives without excessive death of one or more populations of neurons Thus, death of hippocampal and cortical neurons is responsible for the symptoms of Alzheimer’s disease (AD), death of midbrain dopaminergic neurons underlies Parkinson’s disease (PD), From: Pathogenesis of Neurodegenerative Disorders Edited by: M P... EXCITOTOXICITY, AND NEURODEGENERATIVE DISORDERS The evidence implicating apoptosis and excitotoxicity in each of the disorders described below is based on analyses of postmortem tissue from patients, and studies of experimental animal and cell-culture models have strongly implicated neuronal apoptosis Studies of the pathogenic mechanisms of genetic mutations that cause earlyonset autosomal dominant forms of AD,... molecular biological aspects of neurodegenerative disorders, there are as yet no effective treatments for any of the disorders described above However, the available data suggest that several of the most prevalent age-related neurodegenerative disorders may be preventable One such preventive strategy is dietary restriction, which involves a reduced calorie intake with maintenance of micronutrient nutrition... Mattson Fig 1 Examples of morphological and biochemical features of apoptosis During the initiation phase of apoptosis (left), the death signal activates an intracellular cascade of events that may involve increases in levels of oxyradicals and calcium, production of Par-4, and translocation of pro-apoptotic Bcl-2 family members to the mitochondrial membrane The effector phase of apoptosis (middle)... neurons of ALS patients and is associated with increased mitochondrial localization of Bax and decreased association of Bcl-2 Levels of Bax, but not Bcl-2, are increased in spinal-cord motor neurons of ALS patients, and a similar pattern of Bcl-2 family member expression is observed in Cu/Zn-SOD mutant mice Apoptosis involvement in ALS is further suggested by the ability of overexpression of Bcl-2... patients (Fig 2) The number of people with such neurodegenerative disorders is rapidly increasing as average lifespan increases The present chapter, which considers the contributions of apoptosis and excitotoxicity to neurodegenerative disorders, is modified from a recent article on the same topic (Mattson, 2000) NEURONAL APOPTOSIS The death of neurons can be triggered by a variety of stimuli (Table 1) An... disorders is to determine why neurons degenerate and die in specific brain regions in different disorders Major research is underway to understand the etiology and pathogenesis of these disorders to facilitate rational development of effective therapies Numerous partially overlapping hypotheses about the pathogenesis of neurodegenerative diseases include genetic defects, altered membrane metabolism, trace element... against neuronal death The consequences of the death of neurons can be devastating, as in the cases of neurodegenerative disorders such as AD, PD, and ALS There are several prominent anti-apoptotic signaling pathways in neurons Activation of neurotrophic factor receptors can protect neurons against apoptosis by activating receptors linked via kinase cascades to production of cell-survival-promoting proteins... University Department of Clinical Neurosciences, Royal Free Hospital and University College Medical School and Institute of Neurology, University College London, London, UK R GLENN SMITH, Department of Neurology, Baylor College of Medicine, Houston, TX JAMUNA SUBRAMANIAM, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD SHOJI TSUJI, Department of Neurology, Brain Research... neuronal apoptosis and excitotoxicity in neurodegenerative diseases With the discoveries of such disease-initiating factors and specific components of neuronal death and life cascades has come the development of preventative and therapeutic approaches for the neurodegenerative disorders REFERENCES Albensi, B C and Mattson, M P (2000) Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic . Pathogenesis of Neurodegenerative Disorders Pathogenesis of Neurodegenerative Disorders Edited by Mark P. Mattson Edited by Mark P. Mattson HUMANA PRESS HUMANA PRESS Pathogenesis of Neurodegenerative. regulation of cellular ion homeostasis and activation of a stereotyped sequence of events involving mitochondrial dysfunction and activa- tion of specific proteases. Pathogenesis of Neurodegenerative Disorders. the development of valuable animal and cell-culture models of neurodegenerative disorders has allowed the identification of sequences of events within neurons that result in their demise in specific neurodegenerative