Molecular Mechanisms of Neurodegenerative Diseases

426 Pages·2001·1.827 MB·English

by  Marie-Francoise Chesselet

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).
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: [phone]; Fax: [phone];
E-mail: [email protected], or visit our Website at www.humanapress.com
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: [0-89603-804-1/01 $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
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 mecha-
nisms, 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 bet-
ter 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 patho-
physiology of Alzheimer’s disease. This controversial issue is further exam-
ined 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 pro-
tein 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 identifica-
tion 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 dopam-
ine 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