Table Of ContentP
arkinson’s
D
isease
G P
enetics anD athoGenesis
edited By
ted M. Dawson
Johns Hopkins University School of Medicine
Baltimore, Maryland, USA
Preface
Parkinson’s disease is the most common neurodegenerative movement disorder.
A number of advances in genetics, epidemiology, neuropathology, and the deve-
lopment of new experimental models of Parkinson’s disease are providing impor-
tant new insights into the pathogenesis of Parkinson’s disease. Combined, they
have brought spectacular advances and created a renaissance in understanding the
molecular mechanisms of neurodegeneration in Parkinson’s disease. Many of these
advances hold particular promise for mechanistic-based treatments that will slow
or halt the progression of Parkinson’s disease. Currently, there is no text that covers
all the emerging aspects of Parkinson’s disease and for this reason I felt that a
volume dedicated to these topics was timely.
The authors are all leading scientists and clinicians working in the field of
Parkinson’s disease who come from different perspectives. In particular, the authors
have expertise in clinical neurology, genetics, molecular neuroscience, epidemiology,
pathology, and animal models of neurodegenerative diseases. I have tried to draw
together a comprehensive view of the recent major advances in our understanding of
Parkinson’s disease. The first four chapters serve as an introduction to Parkinson’s
disease, they review the major aspects of the disease including neuropathology,
genetics, epidemiology, clinical features and therapy. This is followed by a compre-
hensive review of the genetics of Parkinson’s disease, which leads into chapters on
the major pathogenic hypotheses of Parkinson’s disease, including alpha-synuclein,
PARKIN, DJ-1, PINK-1, LRRK2, mitochondrial dysfunction, and ubiquitin proteaso-
mal dysfunction. Each chapter reviews advances and how these discoveries may
lead to new therapeutic opportunities. The last section discusses animal models and
summarizes the emerging new targets for therapeutics.
I hope that this book is a useful resource for clinicians, researchers, as well as
experts and students alike who have an interest in Parkinson’s disease. Ultimately,
I hope it helps in our efforts to improve the care and ultimately cure the victims of
Parkinson’s disease.
Ted M. Dawson
iii
Contents
Preface iii
Contributors vii
SECTION I: OVERVIEW
1. Neuropathology and Staging of Parkinson’s Disease 1
Dennis W. Dickson
2. Genetics of Parkinson’s Disease 19
Andrew B. Singleton and Jordi Clarimón
3. Epidemiology of Parkinson’s Disease 35
Anabel Chade, Meike Kasten, and Caroline M. Tanner
4. Treatment of Parkinson’s Disease 53
Stanley Fahn
SECTION II: GENETICS
5. Genetics of α-Synuclein 75
Andrew Whittle and Matt Farrer
6. Clinical and Genetic Features of PARKIN-Related Parkinson’s
Disease 83
Ebba Lohmann, Alexis Brice, Alexandra Durr, and Merle Ruberg
7. Genetics: DJ-1 in Parkinson’s Disease 99
Peter Heutink
8. PINK1 Parkinsonism 115
Patrick M. Abou-Sleiman, Miratul M. K. Muqit, and Nicholas W. Wood
9. LRRK2: Genetics and the Pathogenic Mechanisms of Parkinsonism 127
Mark R. Cookson
10. Genetics of Tau in Parkinsonism 135
Rosa Rademakers, Marc Cruts, and Christine van Broeckhoven
11. Genetic Risk Factors for Parkinson’s Disease 153
Sofia A. Oliveira and Jeffery M. Vance
SECTION III: PATHOGENESIS
12. α-Synuclein and Parkinson’s Disease 167
James H. Soper, John Q. Trojanowski, and Virginia M.-Y. Lee
v
vi Contents
13. Tau in Parkinsonian Diseases 187
Daniel M. Skovronsky, Virginia M.-Y. Lee, and John Q. Trojanowski
14. The Role of PARKIN in Parkinson’s Disease 199
Andrew B. West, Valina L. Dawson, and Ted M. Dawson
15. Mitochondrial Complex I Deficiency in Parkinson’s Disease:
A Mechanism for Oxidant-Based Pathogenesis 219
Tatyana V. Votyakova and Ian J. Reynolds
16. The Ubiquitin-Proteasome System in Parkinson’s Disease 237
Leonidas Stefanis
SECTION IV: ANIMAL MODELS
17. Transgenic Models of α-Synucleinopathy 251
Michael K. Lee
18. Mouse Models of Recessive Parkinsonism 269
Matthew S. Goldberg and Jie Shen
19. Drosophila Models of Parkinson’s Disease 287
Leo J. Pallanck and Alexander J. Whitworth
20. Caenorhabditis elegans Models of Parkinson’s Disease 311
Garry Wong
21. The MPTP Model of Parkinson’s Disease 325
Serge Przedborski
22. Rotenone Model for Parkinson’s Disease 351
Ranjita Betarbet and J. Timothy Greenamyre
23. Drug Trials in Animal Models of Parkinson’s Disease 367
Daniel S. Sa and M. Flint Beal
Index 379
Contributors
Patrick M. Abou-Sleiman Department of Molecular Neuroscience, Institute of
Neurology, London, U.K.
M. Flint Beal Department of Neurology and Neuroscience, Weill Medical College of
Cornell University and New York Presbyterian Hospital, New York, New York, U.S.A.
Ranjita Betarbet Center for Neurodegenerative Diseases, Emory University, Atlanta,
Georgia, U.S.A.
Alexis Brice Neurology and Experimental Therapeutics, INSERM U679, Université
Pierre and Marie Curie and Fédération des Maladies du Système Nerveux and
Department de Génétique, Cytogénétique, Groupe Hospitalier Pitié-Salpetriere,
Paris, France
Anabel Chade Department of Clinical Research, The Parkinson’s Institute,
Sunnyvale, California, U.S.A.
Jordi Clarimón Alzheimer’s Laboratory, Sant Pau Hospital, Barcelona, Spain
Mark R. Cookson Cell Biology and Gene Expression Unit, Laboratory of
Neurogenetics, National Institute on Aging, Bethesda, Maryland, U.S.A.
Marc Cruts Department of Molecular Genetics, Neurodegenerative Brain Diseases
Group, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp,
Antwerpen, Belgium
Ted M. Dawson Institute for Cell Engineering, Department of Neurology
and Neuroscience, Johns Hopkins University School of Medicine, Baltimore,
Maryland, U.S.A.
Valina L. Dawson Institute for Cell Engineering, Department of Neurology,
Neuroscience, and Physiology, Johns Hopkins University School of Medicine,
Baltimore, Maryland, U.S.A.
Dennis W. Dickson Departments of Neuroscience and Pathology (Neuropathology),
Mayo Clinic Jacksonville, Jacksonville, Florida, U.S.A.
Alexandra Durr Neurology and Experimental Therapeutics, INSERM U679,
Université Pierre and Marie Curie and Department de Génétique, Cytogénétique,
Groupe Hospitalier, Pitié-Salpetriere, Paris, France
Stanley Fahn Neurological Institute, Columbia University, New York, New York,
U.S.A.
Matt Farrer Neurogenetics, Department of Neuroscience, Mayo Clinic Jacksonville,
Jacksonville, Florida, U.S.A.
Matthew S. Goldberg Center for Neurologic Diseases, Brigham and Women’s
Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A.
J. Timothy Greenamyre Pittsburgh Institute for Neurodegenerative Diseases,
University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
vii
viii Contributors
Peter Heutink Section of Medical Genomics, Department of Human Genetics,
VU University Medical Center, Amsterdam, The Netherlands
Meike Kasten Department of Clinical Research, The Parkinson’s Institute, Sunnyvale,
California, U.S.A.
Michael K. Lee Department of Pathology, Johns Hopkins University School of
Medicine, Baltimore, Maryland, U.S.A.
Virginia M.-Y. Lee Center for Neurodegenerative Disease Research, Department of
Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania,
Philadelphia, Pennsylvania, U.S.A.
Ebba Lohmann Neurology and Experimental Therapeutics, INSERM U679,
Université Pierre and Marie Curie and Fédération des Maladies du Système Nerveux
and Department de Génétique, Cytogénétique, Groupe Hospitalier Pitié-Salpetriere,
Paris, France
Miratul M. K. Muqit Department of Molecular Neuroscience, Institute of Neurology,
London, U.K.
Sofia A. Oliveira Instituto Gulbenkian de Ciência, Oeiras, Portugal
Leo J. Pallanck Department of Genome Sciences, University of Washington, Seattle,
Washington, U.S.A.
Serge Przedborski Department of Neurology, Pathology, and Cell Biology and
Center for Motor Neuron Biology and Disease, Columbia University, New York,
New York, U.S.A.
Rosa Rademakers Department of Molecular Genetics, Neurodegenerative Brain
Diseases Group, Laboratory of Neurogenetics, Institute Born-Bunge, University of
Antwerp, Antwerpen, Belgium
Ian J. Reynolds Neuroscience Drug Discovery, Merck Research Laboratories,
West Point, Pennsylvania, U.S.A.
Merle Ruberg Neurology and Experimental Therapeutics, INSERM U679, Université
Pierre and Marie Curie, Paris, France
Daniel S. Sa Department of Neurology and Neuroscience, Weill Medical College of
Cornell University and New York Presbyterian Hospital, New York, New York, U.S.A.
Jie Shen Center for Neurologic Diseases, Brigham and Women’s Hospital,
Harvard Medical School, Boston, Massachusetts, U.S.A.
Andrew B. Singleton Laboratory of Neurogenetics, National Institute of Aging,
National Institutes of Health, Bethesda, Maryland, U.S.A.
Daniel M. Skovronsky Avid Radiopharmaceuticals, Inc., Philadelphia,
Pennsylvania, U.S.A.
James H. Soper Center for Neurodegenerative Disease Research, Department of
Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania,
Philadelphia, Pennsylvania, U.S.A.
Leonidas Stefanis Section of Basic Neurosciences, Foundation for Biomedical
Research of the Academy of Athens, Athens, Greece
Caroline M. Tanner Department of Clinical Research, The Parkinson’s Institute,
Sunnyvale, California, U.S.A.
Contributors ix
John Q. Trojanowski Center for Neurodegenerative Disease Research,
Department of Pathology and Laboratory Medicine, Institute on Aging, University of
Pennsylvania, Philadelphia, Pennsylvania, U.S.A.
Christine van Broeckhoven Department of Molecular Genetics, Neurodegenerative
Brain Diseases Group, Laboratory of Neurogenetics, Institute Born-Bunge, University
of Antwerp, Antwerpen, Belgium
Jeffery M. Vance Division of Human Genetics, Center for Molecular Genetics and
Genomic Medicine, Miami Institute for Human Genomics, University of Miami,
Miami, Florida, U.S.A.
Tatyana V. Votyakova Division of Immunogenetics, Department of Pediatrics,
University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
Andrew B. West Institute for Cell Engineering, Department of Neurology,
Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.
Andrew Whittle Neurogenetics, Department of Neuroscience, Mayo Clinic
Jacksonville, Jacksonville, Florida, U.S.A.
Alexander J. Whitworth Department of Biomedical Sciences, University of Sheffield,
Sheffield, U.K.
Garry Wong Department of Neurobiology, A.I. Virtanen Institute and Department
of Biochemistry, Kuopio University, Kuopio, Finland
Nicholas W. Wood Department of Molecular Neuroscience, Institute of Neurology,
London, U.K.
