Genotype - Proteotype - Phenotype Relationships in Neurodegenerative Diseases (Research and Perspectives in Alzheimer's Disease)

173 Pages·2005·2.35 MB·English

by  J. Cummings

RESEARCH AND PERSPECTIVES IN ALZHEIMER’S DISEASE
Fondation Ipsen
Editor
Yves Christen, Fondation Ipsen, Paris (France)
Editorial Board
Yves Agid, Hôpital Pitié Salpêtrière, Paris (France)
Albert Aguayo, McGill University, Montreal (Canada)
Brian H. Anderton, Institute of Psychiatry, London (GB)
Raymond T. Bartus, Ceregene, San Diego (USA)
Anders Björklund, University of Lund (Sweden)
Floyd Bloom, Scripps Clinic and Research Foundation, La Jolla (USA)
François Boller, Inserm U 324, Paris (France)
Carl Cotman, University of California, Irvine (USA)
Peter Davies, Albert Einstein College of Medicine, New York (USA)
André Delacourte, Inserm U 422, Lille (France)
Steven Ferris, New York University Medical Center, New York (USA)
Jean-François Foncin, Hôpital Pitié Salpêtrière, Paris (France)
Françoise Forette, Hôpital Broca, Paris (France)
Fred Gage, Salk Institute, La Jolla (USA)
Dmitry Goldgaber, State University of New York Stone Brook (USA)
John Hardy, National Institute of Health, Bethesda (USA)
Jean-Jacques Hauw, Hôpital Pitié Salpêtrière, Paris (France)
Claude Kordon, Institute Necker, Paris (France)
Kenneth S. Kosik, Harvard Medical School, Center for Neurological
Diseases and Brigham and Women’s Hospital, Boston (USA)
Jacques Mallet, Hôpital Pitié Salpêtrière, Paris (France)
Colin L. Masters, University of Melbourne, Parkville (Australia)
Stanley I. Rapoport, National Institute on Aging, Bethesda (USA)
Barry Reisberg, New York University Medical Center, New York (USA)
Allen Roses, Duke University Medical Center, Durham (USA)
Dennis J. Selkoe, Harvard Medical School, Center of Neurological
Diseases and Brigham and Women’s Hospital, Boston (USA)
Michael L. Shelanski, Columbia University, New York (USA)
Pierre-Marie Sinet, Hôpital Necker, Paris (France)
Peter St. George-Hyslop, University of Toronto, Toronto (Canada)
Robert Terry, University of California, La Jolla (USA)
Edouard Zarifi an, Centre Hospitalier Universitaire, Caen (France)
J. Cummings J. Hardy M. Poncet
Y. Christen (Eds.)
Genotype – Proteotype –
Phenotype Relationships
in Neurodegenerative
Diseases
With 20 Figures and 21 Tables
Jeffrey L. Cummings, M.D. John Hardy, Ph.D.
Reed Neurological Research Center, UCLA Laboratory of Neurogenetics
710 Westwood Plaza National Institute on Aging
Box 951769 National Institutes of Health
Los Angeles, CA 90095-1769 Building 35, Rooms 1A1015
USA MSC 3707, Bethesda, MD 20892
E-mail: [email protected] USA
E-mail: [email protected]
Michel Poncet, M.D. Yves Christen, Ph.D.
Neurologie Fondation IPSEN
CHU La Timone Pour la Recherche Thérapeutique
Bd. Jean Moulin 24, rue Erlanger
13385 Marseille Cedex 05 75781 Paris Cedex 16
France France
E-mail: [email protected] e-mail: [email protected]
ISSN 0945-6066
ISBN 3-540-24835-8 Springer-Verlag Berlin Heidelberg New York
Library of Congress Control Number: 2005920457
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is con-
cerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, re-
production on microfi lms or in any other way, and storage in data banks. Duplication of this publication or
parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its
current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable
for prosecution under the German Copyright Law.
Springer-Verlag is a part of Springer Science+Business Media
springeronline.com
© Springer-Verlag Berlin Heidelberg 2005
Printed in Germany
The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply,
even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and
regulations and therefore free for general use.
Product liability: The publishers cannot guarantee the accuracy of any information about dosage and appli-
cation contained in this book. In every individual case the user must check such information by consulting
the relevant literature.
Editor: Dr. Rolf Lange, Heidelberg
Desk Editor: Anne Clauss, Heidelberg
Production: PRO EDIT GmbH, 69126 Heidelberg, Germany
Cover design: design & production, 69121 Heidelberg, Germany
Typesetting: SDS, Leimen, Germany
Printed on acid-free paper 27/3150Re – 5 4 3 2 1 0
Preface
Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s di-
sease, are common afflictions of the elderly and account for a major amount of
morbidity and mortality in older individuals. Less common conditions such as
frontotemporal dementias, dementia with Lewy bodies, progressive supranuclear
palsy, corticobasal degeneration, and Huntington’s disease also are neurodege-
nerative diseases that cause progressive neurological dysfunction and eventual
death. Neurodegenerative diseases produce cognitive, functional and behavioral
disturbances, place tremendous demands on family caregivers, may lead to insti-
tutionalization, and are fatal. Many neurodegenerative diseases are age-related
and the increasing size of the aged population will inevitably result in a greater
number of patients suffering from neurodegenerative conditions unless means
of preventing, delaying or treating these disorders are found. There is an urgent
need to identify tractable therapeutic targets within the pathophysiology of neu-
rodegeneration.
Abnormalities of protein metabolism, including protein misfolding, are incre-
asingly recognized as central to the mechanisms of most neurodegenerative pro-
cesses. Amyloid beta protein production and accumulation is considered central
to the pathophysiology of Alzheimer’s disease; disturbances of proteasome and
alpha- synuclein metabolism are present in Parkinson’s disease, dementia with
Lewy bodies, and multi-system atrophies; disorders of tau or ubiquitin metabo-
lism have been identifi ed in frontotemporal dementias, progressive supranuclear
palsy, and corticobasal degeneration. Abnormalities of huntingtin are characteri-
stic of Huntington’s disease. Other neurodegenerations have uniquely associated
protein abnormalities. Prion disorders also result in abnormal protein deposits
and self-propagating protein misfolding appears to be the major pathophysiolo-
gic event in prion diseases. Recent advances in understanding the role of prote-
in dysmetabolism in neurodegeneration was the theme of the Fondation IPSEN
meeting (September 13, 2004) addressing Genotype-Proteotype-Phenotype rela-
tionships. Experts from international laboratories contributed to the conference
and the current volume to produce a comprehensive overview of the role of pro-
tein misfolding in neurodegeneration. Links between genotype and protein cha-
racteristics and between proteotype and clinical phenomenology were discussed
across diseases categories. Progress in understanding the role of abnormalities of
protein metabolism may lead to the identifi cation of biological markers relevant
to disease monitoring and to the development of new therapeutic agents capable
of modifying and ameliorating basic neurodegenerative mechanisms.
VI Preface
Acknowledgement
The editors wish to thank Jacqueline Mervaillie for organizing the meeting in Pa-
ris and Astrid de Gerard, Katrina Kerr and Mary-Lynn Gage for the editing of the
book.
Los Angeles, California, Jeffrey L. Cummings
January 2005
Contents
Neurodegenerative Disorders as Proteinopathies:
Phenotypic Relationships
Jeffrey L. Cummings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Towards a Molecular Classification of Neurodegenerative Disease
John Hardy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Racial and Ethnic Influences on the Expression
of the Genotype in Neurodegenerative Diseases
Katrina Gwinn-Hardy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Causes and Consequences of Oxidative Stress
in Neurodegenerative Diseases
Domenico Praticò . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Early Onset Familial Alzheimer’s Disease:
Is a Mutation Predictive of Pathology?
Douglas Galasko . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Identification of Genes that Modify the Age of Onset
in a Large Familial Alzheimer’s Disease Kindred
Alison M. Goate, Pau Pastor, Catherine M. Roe, Joanne Norton,
Sumi Chakraverty, Francisco Lopera, Kenneth S. Kosik . . . . . . . . . . . . . . . . . . . . 61
Variable Phenotype of Alzheimer’s Disease with Spastic Paraparesis
Helena Karlstrom, William S. Brooks, John B.J. Kwok,
Jillian J. Kril, Glenda M. Halliday, Peter R. Schofield . . . . . . . . . . . . . . . . . . . . . . 73
Presenilin Mutations: Variations in the Behavioral Phenotype
with an Emphasis on the Frontotemporal Dementia Phenotype
Neill R. Graff-Radford . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Frontotemporal Dementias: Genotypes and Phenotypes
Virginia M.-Y. Lee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
VIII Contents
Chromosome 17-Linked Frontotemporal Dementia
with Ubiquitin-Positive, tau-Negative Inclusions
Rosa Rademakers, Julie van der Zee, Samir Kumar-Singh, Bart Dermaut,
Marc Cruts, Christine Van Broeckhoven . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Variations of the Phenotype in Frontotemporal Dementias
N. L. Foster, R. E. Koeppe, B. J. Giordani, T. E. Nichols, A. P. Lieberman . . . . . . 139
Phenotype/Genotype Correlations in Parkinson’s Disease
Alexis Brice, Ebba Lohmann, Pablo Ibanez, Magali Periquet, Sophie Laine,
Béatrice Debarges, Suzanne Lesage, and Alexandra Dürr . . . . . . . . . . . . . . . . . . 153
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Contributors
Brice, Alexis
INSERM Unit 289 and Département de Génétique,
Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, AP-HP
47 boulevard de l’Hôpital, 75651 Paris Cedex 13
France
Brooks, William S
Prince of Wales Medical Research Institute, University of New South Wales,
Barker Street, Randwick, Sydney
Australia
Chakraverty, Sumi
Department of Psychiatry, Washington University School of Medicine,
Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110
USA
Cruts, Marc
Department of Molecular Genetics,
Flanders Interuniversity Institute for Biotechnology (VIB),
University of Antwerp (UA), 2610 Antwerpen
Belgium
Cummings, Jeffrey L.
Departments of Neurology and Psychiatry and Biobehavioral Sciences,
David Geffen School of Medicine at UCLA, Los Angeles, CA, USA,
Reed Neurological Research Center, UCLA,
710 Westwood Plaza, Box 951769, Los Angeles, CA 90095-1769
USA
Debarges, Béatrice
INSERM Unit 289, Département de Génétique, Cytogénétique et Embryologie
Hôpital de la Pitié-Salpêtrière, AP-HP, 47 boulevard de l’Hôpital,
75651 Paris Cedex 13
France
X Contributors
Dermaut, Bart
Department of Molecular Genetics,
Flanders Interuniversity Institute for Biotechnology (VIB),
University of Antwerp (UA), 2610 Antwerpen,
Belgium
Dürr, Alexandra
INSERM Unit 289, Département de Génétique
Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, AP-HP,
47 boulevard de l’Hôpital, 75651 Paris Cedex 13
France
Foster, Norman L.
Department of Neurology, University of Michigan,
1920 Taubman Center
1500 E. Medical Center Dr. Ann Arbor, MI 48109-0316,
USA
Galasko, Douglas
Professor, Department of Neurosciences, UCSD,
and Staff Physician, Veterans Affairs Medical Center,
3350 La Jolla Village Drive, San Diego CA 92161,
USA
Giordani, B. J.
Department of Psychiatry, University of Michigan
Ann Arbor, MI, 48109,
USA
Goate, Alison M.
Department of Psychiatry, Washington University School of Medicine,
Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110,
USA
Graff-Radford, Neill R.
Mayo College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224
USA
Gwinn-Hardy, Katrina
National Institute of Neurological Disorders and Stroke,
National Institutes of Health, Bethesda, MD 20892
USA
Halliday, Glenda M
Prince of Wales Medical Research Institute, University of New South Wales,
Barker Street, Randwick , Sydney,
Australia