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Molecular Mechanisms of Neurodegenerative Diseases Edited by Marie-Françoise Chesselet, , MD PhD HUMANA PRESS Molecular Mechanisms of Neurodegenerative Diseases C ontemporary C linical Series Editors: N Ralph Lydic and euroscience Helen A. Baghdoyan Molecular Mechanisms of Neurodegenerative Diseases edited by Marie-Françoise Chesselet, 2000 Contemporary Clinical Neuroscience Molecular Mechanisms of Neurodegenerative Diseases Marie-Françoise Chesselet, MD, PhD Reed Neurological Research Center, School of Medicine, University of California, Los Angeles, Los Angeles, CA 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 permis- sion 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. Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published and to describe generally accepted practices. The contributors herein have care- fully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in govern- ment regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication. This publication is printed on acid-free paper. (cid:39) ANSI Z39.48-1984 (American Standards Institute) Permanence of Paper for Printed Library Materials. Cover design by Patricia F. Cleary. Cover photos, clockwise from upper right: from Fig. 3, Chapter 12 (Opal and Paulson); from Fig. 3, Chapter 1 (Klein); from Fig. 1, Chapter 11 (Orr and Zoghbi); from Fig. 4, Chapter 1 (Klein). 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Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 Library of Congress Cataloging-in-Publication Data Molecular mechanisms of neurodegenerative diseases / [edited by] Marie-Francoise Chesselet. p. cm. -- (Contemporary clinical neuroscience) Includes bibliographical references and index. ISBN 0-89603-804-1 (alk. paper) 1. Nervous system--Degeneration--Molecular aspects. 2. Molecular neurobiology. I. Chesselet, Marie-Francoise. II. Series. [DNLM: 1. Neurodegenerative Diseases--genetics 2. Neurodegenerative Diseases--physiopathology ] RC365 .M64 2000 616.8'047--dc21 00-032041 Preface The field of neurodegenerative diseases is undergoing an unprecedented revolution. The past decade has seen the identification of new mutation mechanisms, such as triplet repeat expansions, and new genes causing familial forms of common neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases. Cellular and animal models based on this genetic information are now available and, importantly, common mechanisms are rapidly emerging among diseases that were once considered unrelated. The field is poised for the development of new therapies based on high throughput screenings and a better understanding of the molecular and cellular mechanisms leading to neurodegeneration. Molecular Mechanisms of Neurodegenerative Diseases reviews recent progress in this exploding field. By nature, such a book cannot be all inclu- sive. It focuses on Alzheimer’s, Parkinson’s, and CAG triplet repeat diseases. In the first chapter, Bill Klein reviews the role of A(cid:96) toxicity in the pathophysiology of Alzheimer’s disease. This controversial issue is further examined in the context of transgenic models of Alzheimer’s disease by LaFerla and colleagues. Sue Griffin and Robert Mrak, and Caleb Finch and collabora- tors, then examine the role of glial cells and inflammation in Alzheimer’s disease; a review of the role of proteolysis in the generation of abnormal protein fragments by Hook and Mende-Mueller follows. Therapeutic opportuni- ties offered by a better understanding of Alzheimer’s disease pathophysiology are examined by Perry Molinoff and his colleagues at Bristol-Myers Squibb. The chapter on proteolysis by Hook and Mende-Mueller identifies one of the recurring themes that is appearing among neurodegenerative diseases: the formation of abnormal protein fragments, whose misfolding may lead to a cas- cade of cellular defects, ultimately leading to cell death. Similarities between pathological processes in Parkinson’s, Alzheimer’s, and related diseases is also the theme of the chapter by Virginia Lee, John Trojanowski, and collabo- rators, which discusses the role of Tau and synuclein. Despite the identification of mutations in synuclein, and the presence of synuclein in Lewy bodies, the pathophysiology of Parkinson’s disease, however, remains poorly under- stood. Joel Perlmutter and his colleagues review the information we have recently gained on the progression of the disease from brain imaging studies. v vi Preface BethAnn McLaughlin and Russell Swerdlow then examine the role of dopamine and of mitochondrial dysfunction, respectively, in neurodegeneration. The last chapters of the book deal with different and complementary aspects of CAG repeat diseases, including SCA1 (Orr and Zoghbi), SCA3 (Opal and Paulson), SBMA (Merry), and Huntington’s disease. Chesselet and Levine compare the different mouse models of Huntington’s disease, MacDonald and colleagues review the role of proteins interacting with huntingtin, and George Jackson discusses the potential of fly genetics to iden- tify the molecular mechanisms of neurodegenerative diseases. Despite their differences in focus, many chapters of Molecular Mecha- nisms of Neurodegenerative Diseasesoverlap, presenting the variety of view- points that pervade this dynamic field. Evidently, since new data appear every day, the chapters in a book can only provide the basis for understanding ongo- ing research. It is hoped that the ideas and concepts presented here will lead, within a few short years, to therapies that prevent, delay the onset, slow the progression, or even cure these devastating neurodegenerative illnesses. Marie-Françoise Chesselet, MD, PhD Dedication This book is dedicated to the memory of Roger Chesselet, who believed that scientific discoveries happen at the junction of multidisciplinary fields, and of John B. Penney, who dedicated his life to finding a cure for neurodegenerative diseases and whose untimely death prevented him from contributing to this book. vii Contents Preface ...................................................................................................................v Contributors ........................................................................................................xi 1 A(cid:96) Toxicity in Alzheimer’s Disease..................................................................1 William L. Klein 2 Transgenic Models of Alzheimer’s Disease...................................................51 Michael C. Sugarman, Steven F. Hinton, and Frank M. LaFerla 3 Glial Cells in Alzheimer’s Disease..................................................................73 Robert E. Mrak and W. Sue T. Griffin 4 Inflammation in Alzheimer’s Disease............................................................87 Caleb E. Finch, Valter Longo, Aya Miyao, Todd E. Morgan, Irina Rozovsky, Yubei Soong, Min Wei, Zhong Xie, and Hadi Zanjani 5 Proteolysis in Neurodegenerative Diseases................................................111 Vivian Y. H. Hook and Liane Mende-Mueller 6 Treatment Approaches for Alzheimer’s Disease........................................131 Michael Gold, Kevin M. Felsenstein, and Perry Molinoff 7 Tau and (cid:95)-Synuclein in Neurodegenerative Diseases ..............................151 Benoit I. Giasson, Christina A. Wilson, John Q. Trojanowski, and Virginia M. Y. Lee 8 PET Investigations of Parkinson’s Disease..................................................177 Tamara Hershey, Stephen M. Moerlein, and Joel S. Perlmutter 9 Dopamine Neurotoxicity and Neurodegeneration....................................195 BethAnn McLaughlin 10 Mitochondria and Parkinson’s Disease........................................................233 Russell H. Swerdlow 11 Pathophysiology of SCA1...............................................................................271 Harry T. Orr and Huda Y. Zoghbi 12 Pathophysiology of SCA3...............................................................................285 Puneet Opal and Henry Paulson 13 Pathophysiology of Spinal and Bulbar Muscular Atrophy......................307 Diane E. Merry 14 Mouse Models of Huntington’s Disease......................................................327 Marie-Françoise Chesselet and Michael S. Levine ix