Recent Advances in Parkinson’S Disease: Translational and Clinical Research

353 Pages·2010·9.213 MB·English

by  Anders Björklund and M. Angela Cenci (Eds.)

PROGRESS IN BRAIN RESEARCH
VOLUME 184
RECENT ADVANCES IN PARKINSON’S

DISEASE: TRANSLATIONAL AND

CLINICAL RESEARCH

EDITED BY
ANDERS BJO¨ RKLUND
Wallenberg Neuroscience Centre

Division of Neurobiology

Lund University

Lund, Sweden

M. ANGELA CENCI
Basal Ganglia Pathophysiology Unit

Department of Experimental Medical Science

Lund University

Lund, Sweden

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ISSN: 0079-6123
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List of Contributors

S.B. Rangasamy, Departments of Neurological Sciences and Neurosurgery, Rush University Medical
Center, Chicago, IL, USA
R.A.E. Bakay, Departments of Neurological Sciences and Neurosurgery, Rush University Medical
Center, Chicago, IL, USA
R.A. Barker, Cambridge Centre for Brain Repair, Robinson Way, Cambridge, UK
C.J. Barnum, Department of Physiology, Emory University School of Medicine, Atlanta, GA, USA
A. Björklund, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund
University, Lund, Sweden
T. Björklund, Brain Repair and Imaging in Neural Systems, Department of Experimental Medical
Science, Lund University, Lund, Sweden
D.J. Brooks, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital,
London, UK
J.M. Brotchie, Toronto Western Research Institute, Toronto Western Hospital, Toronto, ON, Canada
P. Brundin, Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden
J.R. Cannon, Pittsburgh Institute for Neurodegenerative Diseases, Department of Neurology, University
of Pittsburgh, Pittsburgh, PA, USA
E.A. Cederfjäll, Brain Repair and Imaging in Neural Systems, Department of Experimental Medical
Science, Lund University, Lund, Sweden
K.R. Chaudhuri, National Parkinson Foundation Centre of Excellence, Kings College Hospital and
University Hospital Lewisham; and Kings College and Institute of Psychiatry, London, UK
M.-F. Chesselet, Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA,
USA
M. Decressac, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund
University, Lund, Sweden
S.B. Dunnett, Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, South Wales, UK
D. Eidelberg, Center for Neurosciences, The Feinstein Institute for Medical Research; and Departments
of Neurology and Medicine, North Shore University Hospital, Manhasset, NY, USA
S.H. Fox, Division of Neurology, University of Toronto; and Toronto Western Research Institute,
Toronto Western Hospital, Toronto, ON, Canada
J.T. Greenamyre, Pittsburgh Institute for Neurodegenerative Diseases, Department of Neurology,
University of Pittsburgh, Pittsburgh, PA, USA
M. Guo, Department of Neurology, Department of Molecular and Medical Pharmacology, Brain
Research Institute, David Geffen School of Medicine, Los Angeles, CA, USA
D. Kirik, Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science,
Lund University, Lund, Sweden
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J.H. Kordower, Departments of Neurological Sciences and Neurosurgery, Rush University Medical
Center, Chicago, IL, USA
R. Kuriakose, Pacific Parkinson’s Research Centre, University of British Columbia and Vancouver
Coastal Health, Vancouver, BC, Canada
E.L. Lane, Welsh School of Pharmacy, Cardiff University, Cardiff, South Wales, UK
M. Lelos, School of Biosciences, Cardiff University, Cardiff, South Wales, UK
A.M. Lozano, Division of Neurosurgery, University of Toronto, Toronto Western Hospital, Toronto, ON,
Canada
I. Magen, Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
P. Odin, Department of Neurology, Skane University Hospital, Lund, Sweden; and Department of
Neurology, Central Hospital Bremerhaven, Bremerhaven, Germany
M. Parmar, Neurobiology Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden
N. Pavese, MRC Clinical Sciences Centre and Department of Medicine, Imperial College London,
London, UK
P. Piccini, Centre for Neuroscience and MRC Clinical Sciences Centre, Faculty of Medicine,
Hammersmith Hospital, Imperial College London, UK
M. Politis, Centre for Neuroscience and MRC Clinical Sciences Centre, Faculty of Medicine,
Hammersmith Hospital, Imperial College London, UK
F.A. Ponce, Division of Neurosurgery, University of Toronto, Toronto Western Hospital, Toronto, ON,
Canada; Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph’s Hospital and
Medical Center, Phoenix, AZ, USA
K. Soderstrom, Departments of Neurological Sciences and Neurosurgery, Rush University Medical
Center, Chicago, IL, USA
A.J. Stoessl, Pacific Parkinson’s Research Centre, University of British Columbia and Vancouver Coastal
Health, Vancouver, BC, Canada
C.C. Tang, Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, NY, USA
M.G. Tansey, Department of Physiology, Emory University School of Medicine, Atlanta, GA, USA
A. Ulusoy, Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science,
Lund University, Lund, Sweden
C. Winkler, Department of Neurology, University Hospital Freiburg, Freiburg, Germany
Preface
Research on Parkinson’s disease (PD) is one of the most dynamic fields of modern neuroscience. It is an
excellent example of how clinical and basic research can fruitfully interact and inspire each other in a truly
translational way. During the decades after the discovery of dopamine in the late 1950s, the field was
dominated by pharmacological and neurochemical approaches. Since the discovery of the role of
a-synuclein and its role in PD pathogenesis in the late 1990s, PD research has entered a new exciting
phase of development and its scope has broadened to include dynamic molecular and genetic approaches.
This had led to the discovery of further genetic mutations accounting for familial forms of the disease
(Parkin, DJ-1, Pink-1, and leucine-rich repeat kinase 2) and spurred intense molecular biological investi­
gations on the mechanisms of neurodegeneration in PD. In addition to molecular genetics, other fields of
PD research have undergone a dramatic development during the past 20 years. Significant progress has
been made modeling PD in animals both on a symptomatic level and on a mechanistic perspective. The
current availability of a diversified range of models in different species provides neuroscientists with
articulate tools to study molecular mechanisms, test pathophysiological hypotheses, and identify new
treatment principles. The discovery that PD motor symptoms and treatment-induced dyskinesias are
dramatically ameliorated by high-frequency stimulation of some deep basal ganglia nuclei has prompted
efforts on the part of both neurophysiologists and computational neuroscientists to decipher the basic
neural operations of the basal ganglia in health and disease. Finally, technological developments in the
area of brain imaging have provided exciting new opportunities for pathophysiological investigations,
differential diagnosis, and treatment monitoring in PD patients.
These two companion volumes of Progress in Brain Research (Volumes 183 and 184) were composed to
capture all the richness and complexity of PD as a topic for basic, translational, and clinical investigation.
A year ago, when we approached leading researchers in the different subfields to contribute, the vast
majority of the invited authors enthusiastically accepted the invitation and delivered contributions that
turned out to represent the utmost state of the art in each given field. It is with great pleasure and pride
that we now present this collection of review Chapters to a broad audience of readers.
The chapters have been grouped in two volumes and five sections. The first volume covers basic and
molecular investigations of the mechanisms of neurodegeneration in PD (Section I: Genetic and molecular
mechanisms of neurodegeneration in PD) and the secondary adaptations that affect the basal ganglia at
both the single cell level and the system level (Section II: Cellular and system-level pathophysiology of the
basal ganglia in PD).
The second volume focuses on translational and clinical aspects of PD research, reviewing animal
models of PD from Drosophila to nonhuman primate species (Section I: Animal models of PD), the
very dynamic area of functional neuroimaging (Section II: Exploring PD with brain imaging), and the most
challenging therapeutic developments (Section III: Frontiers in PD treatment).
Like no other neurological disease, PD is inspiring enormously diversified research themes and
approaches in a way that would have been impossible to foresee some 10 years ago. An increasing number
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of investigators, also from areas outside neuroscience, have joined the PD research community and are
now contributing to the richness and diversity of this field. Over the last 15 years, several international PD
patient-initiated, nonprofit organizations have dramatically improved the funding possibilities for this area
of research which is now advancing at an extremely rapid pace. It is our hope that this formidable
development of knowledge and technologies will deliver novel options for treatment – and eventually a
cure – for all who suffer from this disease.
In closing we would like to express our warmest thanks to all the authors for their outstanding
contributions and to Gayathri Venkatasamy, our Developmental Editor at Elsevier, for her expert and
patient assistance.
Lund, June 11, 2010
Anders Bj o¨rklund
M. Angela Cenci
SECTION I

Animal models of PD
A. Bjorklund and M. A. Cenci (Eds.)

Progress in Brain Research, Vol. 184

ISSN: 0079-6123

Copyright � 2010 Elsevier B.V. All rights reserved.

CHAPTER 1
What have we learned from Drosophila models
’
of Parkinson s disease?
Ming Guo(cid:1)
Department of Neurology, Department of Molecular and Medical Pharmacology, Brain Research Institute,

David Geffen School of Medicine, Los Angeles, CA, USA

Abstract: Parkinson’s disease (PD) is characterized clinically by motor symptoms such as resting tremor,
slowness of movement, rigidity, and postural instability, and pathologically by the degeneration of multiple
neuronal types, including, most notably, dopaminergic (DA) neurons in the substantia nigra. Current
medical treatment for PD focuses on dopamine replacement, but dopamine replacement ultimately fails
and has little effect on a variety of dopamine-independent symptoms both within and outside the nervous
system. To develop new therapies, we need to aim at alleviating widespread cellular defects in addition to
those focusing on DA neuronal survival. Recent observations in Drosophila have provided important
insights into the cellular basis of PD pathogenesis through the demonstration that two genes associated
with familial forms of PD, pink1 and parkin, function in a common pathway. In this pathway, pink1
functions upstream of parkin to regulate mitochondrial fission/fusion dynamics and normal mitochondrial
function. Subsequent observations in both fly and mammalian systems show that these proteins are
important for sensing mitochondrial damage and recruiting damaged mitochondria to the quality
control machinery for subsequent removal. This chapter reviews these findings, as well as studies of DJ­
1 and Omi/HtrA2, two additional genes associated with PD that have also been implicated to regulate
mitochondrial function. The chapter ends by discussing how Drosophila can be used to probe further the
functions of pink1 and parkin and the regulation of mitochondrial quality more generally. In addition to
PD, defects in mitochondrial function are associated with normal aging and with many diseases of aging.
Thus, insights gained from the studies of mitochondrial dynamics and quality control in Drosophila are
likely to be of general significance.
Keywords: Parkinson’s disease; Drosophila; PINK1; parkin; mitochondria; dopaminergic neurons; animal
model; mitochondrial fusion and fission; mitophagy
(cid:1) Corresponding author.
Tel.: þ1-310-2069406;
E-mail: [email protected]
DOI: 10.1016/S0079-6123(10)84001-4 3
4
Parkinson’s disease is a disorder involving more consequences in multiple tissues, is crucial for
than dopaminergic neuronal loss pathogenesis in at least some forms of PD.
Parkinson’s disease (PD) is the second most
common neurodegenerative disorder affecting 5% Familial forms of PD
of people over the age of 80. N and no treatments
can definitively halt the progression of the disease. Although once believed to be solely an environ­
Thus, understanding the disease mechanisms and mental disease, over the past decade mutations in
identifying new therapeutic strategies are crucial five genes have been definitively shown to med­
for treating patients with PD. Clinical features of iate familial forms of PD. Mutations in PARKIN
PD include “motor symptoms” such as resting tre­ (PARK2) (Kitada et al., 1998), DJ-1 (PARK7)
mor, slowness of movement, rigidity, and postural (Bonifati et al., 2003), and PTEN-induced kinase 1
instability. PD is characterized pathologically by the (PINK1, PARK6) (Valente et al., 2004) are asso­
degeneration of multiple neuronal types including, ciated with autosomal recessive forms of PD,
most notably, dopaminergic (DA) neurons in the while mutations in a-Synuclein (PARK1 (Poly­
substantia nigra of the midbrain (Dauer and Przed­ meropoulos et al., 1997) and PARK4 (Singleton
borski, 2003). The mainstay of current medical et al., 2003)) and Leucine-rich repeat kinase 2
treatment for PD is dopamine replacement. How­ (LRRK2)/Dardarin (PARK8) (Paisan-Ruiz et al.,
ever, this treatment becomes less effective over time 2004; Zimprich et al., 2004) are associated with
and is often associated with intolerable side effects. autosomal dominant forms of the disease. Muta­
In addition, PD patients also present with a variety tions in ATP13A2 (PARK9), which encodes a
of non-motor symptoms (Simuni and Sethi, 2008). lysosomal ATPase, have been found in an atypi­
These include including dementia, which occurs in cal, autosomal recessive parkinsonism (Ramirez
one third of patients, psychiatric symptoms, such as et al., 2006); however, the clinical manifestations,
depression, anxiety, obsession, and sleep disruption, of this disease are quite distinct from PD (Schnei­
and symptoms outside of the nervous system, der et al., 2010). The “PARK” here refers to
including skin lesions and musculoskeletal abnorm­ genetic loci that have been identified from family
alities. Some of these non-motor symptoms may be linkage studies for PD (Hardy et al., 2009).
more debilitating than the motor impairment, but Together, these single gene-mediated, Mendelian
they do not usually respond to dopamine replace­ forms of the disease represent about 10–15% of all
ment. In addition, pathology of many non-DA neu­ PD cases. The clinical features of at least some of
rons, including olfactory and brain stem neurons, these familial forms of PD bear significant similar­
predates that of DA neurons (Braak et al., 2003). ity to those of sporadic forms. Thus, the hope is
In short, PD is a multi-system disease affecting more that studies of familial forms of the disease will
than DA neurons. Therefore, therapies targeted to also provide insights into the more prevalent
DA neurons or their targets (such as dopamine sporadic forms. Formal nomenclature has utilized
replacement, cell transplantation, and deep brain the term PD for sporadic PD and parkinsonism for
stimulation) can provide some therapeutic benefit genetic forms of PD. This is largely based on the
to patients, particularly with respect to the motor fact that the cause of PD was previously thought
symptoms. However, a true cure requires that to be non-genetic and solely environmental, a
we develop therapies that target the underlying notion that is clearly no longer believed to be
cellular defects. A prerequisite for this work is that true (Hardy et al., 2006). It is also probable that
we understand the pathogenesis of PD at the as research advances, more genes that mediate
cellular and molecular levels. As will be described Mendelian forms of PD and multigenic forms of
below, mitochondrial dysfunction, which has PD will be identified. Thus, to simplify, this