Download 2003-2005 - Parkinson Canada

Parkinson Society Canada
National Research Program Awards
for 2003-2005 Cycle
Granting period
July 1, 2003 – June 30, 2005
OPERATING GRANTS
Researcher: Anurag Tandon
Name of Project: Organization and Disassembly of Alpha-Synuclein Complexes in Human Cells
Institution: Centre for Research in Neurodegenerative Diseases, University of Toronto
Amount Year One: $50,000
Amount Year Two: $50,000
Total Awarded: $100,000
Lay Summary: The causes of Parkinson’s disease are poorly understood and current therapies which
provide symptomatic relief, based on increasing dopamine levels in the brains of patients, do not alter
the normal progression of the disease. A key factor involved in PD is alpha-synuclein, which is a small
protein normally found in high abundance in all brains. However, in PD and other neurodegenerative
diseases known collectively as synucleinopathies, alpha-synuclein aggregates into sticky insoluble
deposits within neurons. It is unknown how or why alpha-synuclein forms these insoluble deposits.
This proposal aims to characterize the cellular machinery that regulates alpha-synuclein interactions
with intracellular membranes and with other proteins in human dopaminergic cells. Studies in my
laboratory show that alpha-synuclein forms large protein complexes that are regulated by neuronal
activity. These previously unknown alpha-synuclein complexes are detectable in human secretory
cells, and in rodent and human brains. Their presence in normal neurons suggests that the complexes
are important for alpha-synuclein’s biological role. We predict that these large alpha-synucleincontaining complexes are early precursors to the sticky aggregates seen in PD brains, and
understanding the organization and assembly of theses novel complexes in dopaminergic cells will
provide new and fundamental insights into alpha-synuclein function and dysfunction in PD.
Researcher: Daniel Lévesque, Claude Rouillard, Paul Bédard and Thérese DiPaolo
Name of Project: The transcription factors Nur77 and Retinoid X Receptor (RXR): putative new
players involved in motor dysfunctions associated with Parkinson’s disease and L-DOPA therapy
Institution: Neuroscience Research Center, Laval University
Amount Year One: $50,000
Amount Year Two: $50,000
Total Awarded: $100,000
Lay Summary: Levodopa therapy is the cornerstone of the treatment of Parkinson’s disease (PD).
However, motor fluctuations and dyskinesias appear after prolonged treatment and seriously limit the
benefice of this therapy. The mechanism responsible for this reduced efficacy remain elusive. We have
identified a new set of genes that seems to be associated with motor functions. These genes are
members of the nuclear receptor family of transcription factors, which are responsible for the control of
gene expression and possibly involved in cellular maladaptation resulting from chronic drug treatment.
Investigation of these genes in PD will improve our understanding of the pathophysiology of the disease
and on the generation of side-effects after L-DOPA therapy.
Researcher: David Grimes
Name of Project: Parkinson’s Genetics in a Canadian Cohort
Institution: Ottawa Hospital
Amount Year One: $50,000
Amount Year Two: $50,000
Total Awarded: $100,000
Lay Summary: The cause of Parkinson’s disease remains unknown for most affected individuals.
However, specific genetic defects have now been shown to cause the disease in a subgroup of
patients. Currently, genetic defects have been identified in five different genes (alpha-synuclein,
ubiquitin C-terminal hydrolase, DJ1 and NR4A2). A sixth gene (NF-M) has also recently been
implicated in one French-Canadian Parkinson’s patient. It is currently unknown if it could be playing a
role in other patients, especially those of similar heritage. We have been studying a large family where
13 individuals have been affected with Parkinson’s disease. We are looking for a novel gene defect in
this family and have narrowed down the region where the disease-causing gene is located.
Identification and verification of this disease gene will be accomplished through the collection of DNA
from French-Canadian individuals and families affected with Parkinson’s disease. Using markers linked
to our region in our large family, we will look for an association between certain alleles in our FrenchCanadian cohort. In addition, we will be investigating the role of NF-M gene could be playing in our
Canadian cohort. Identifying and studying these gene changes will provide important clues that will
further our understanding of the possible mechanisms that cause Parkinson’s disease and by
understanding these mechanisms, will ultimately result in a cure.
PILOT PROJECT PROGRAM GRANTS
Friedman Grant
Researcher: David Park
Name of Project: Pathways by which DJ-1, a gene linked to familial PD, mediate dopaminergic loss
Institution: Ottawa Hospital
Amount Year One: $45,000
Amount Year Two: n/a – one year grant
Total Awarded: $45,000
Lay Summary: Parkinson’s disease is a devastating neurodegenerative condition due to loss of a
small population of neurons in a specific area of the brain called the substantial nigra. Recent evidence
has linked a gene called DJ-1 to the development of PD. However, the manner by which this gene
participates in brain cell loss is not known. We propose to initiate a series of studies that will begin to
explore the mechanism by which DJ-1 mediate neuron loss occurs. First, we will determine how
expression of loss of DJ-1 affects neurons exposed to toxic substances known to cause Parkinsonian
symptoms. We will then determine how localization of DJ-1 inside the cell may affect brain cell death or
survival.
Researcher: Michael Rathbone & Eva Werstiuk
Name of Project: Protection against MPP+-induced apoptosis by non-adenine based purines
Institution: McMaster University
Amount Year One: $45,000
Amount Year Two: n/a – one year grant
Total Awarded: $45,000
Lay Summary: In Parkinson’s disease, recent evidence indicates that some nerve cells die through a
process of programmed cell death or ‘apoptosis”. Guanosine, when present at high concentrations
outside the cells, reduces apoptosis. We will determine whether guanosine can aid in Parkinson’s
disease treatment, by inhibiting apoptosis. MPP+, a chemical that induces a Parkinson’s disease-like
condition in mammals, alters the function of the energy creating system of the cell by inhibiting a key
component and thus triggers apoptosis. We will determine if guanosine can inhibit this apoptosis and
thus potentially lead to an approach to treating Parkinson’s disease.
Researcher: Anatol Feldman
Name of Project: Virtual reality for gait initiation and control in Parkinson patients
Institution: University of Montreal
Amount Year One: $45,000
Amount Year Two: n/a – one year grant
Total Awarded: $45,000
Lay Summary: When subjects initiate and maintain walking, visual images are appropriately
transformed by the brain to preserve the sense that the environment is motionless. We hypothesise
that the initiation of this sensory process is deficient in some Parkinson subjects, resulting in difficulties
in movement initiation. To test this hypothesis and facilitate the postural transitions related to gait
initiation, Parkinson patients will be immersed in a virtual reality environment that will be displaced at a
controlled speed during the delay period between the signal to move and movement onset. By
addressing the basic question on the relationship between perception and action, this project can
potentially help in the rehabilitation of Parkinson patients.
Researcher: Lennard P. Niles
Name of Project: Neuroprotection by Neural Stem Cells and Melatonin in a Model of Parkinson's
Disease
Institution: McMaster University
Amount Year One: $45,000
Amount Year Two: n/a – one year grant
Total Awarded: $45,000
Lay Summary: Parkinson’s disease (PD) is caused by the loss of brain cells which produce dopamine,
a chemical which regulates movement. Although drugs provide symptomatic relief, there are no
treatments which can prevent the onset of PD or stop its progression. The effects of treatment with a
neuroprotective hormone, in conjunction with transplantation of stem cells into the brain of an animal
model of PD, will be examined. Hopefully the neuron-supportive agents produced by these stem cells
will protect residual dopamine-producing cells and induce their regeneration. A reversal of the
functional abnormalities exhibited by the PD model would indicate novel therapeutic approaches.
NEW INVESTIGATOR AWARD PROGRAM
Researcher: Christian Duval
Name of Project: Tri-dimensional Kinematic characterization of drug-induced dyskinesia. A study of
young-onset versus elderly patients
Institution: Brock University
Amount Year One: $24,300
Amount Year Two: $25,500
Total Awarded: $49,800
Lay Summary: Clinical experience suggests that drug-induced dyskinesia (DID) appears much earlier
in patients with young onset Parkinson’s disease (YOPD). This difference in the onset may depend on
differences in the pathophysiology of PD for these patients. We hypothesize that these differences may
be visible in (a) the movement characteristics of DID, and (b) its influence on the voluntary movement
patients. Accordingly, we intend to determine if movement patterns of YOPD patients differ from those
in late-onset Parkinson’s disease (LOPD) patients, and if DID affects differently the motor performance
of YOPD patients. The proposed studies will allow us to improve our understanding of movement
pattern of DID and their impact on voluntary movement. In addition, they will allow us to determine if
the movement pattern of DID and its impact on voluntary movement differ between YOPD and LOPD.
These studies will also ultimately allow for the development of robust methods for objective assessment
of new drug and surgical treatments.
Researcher: Francesca Cicchetti
Name of Project: Anti-inflammatory drug treatment in animal models of Parkinson’s disease: a novel
therapeutic approach
Institution: Laval University
Amount Year One: $40,000
Amount Year Two: $40,000
Total Awarded: $80,000
Lay Summary: One person in 200 will get Parkinson’s disease (PD) during their lifetime with
increasing risk with age (1 in every 100 persons over 60 has PD) and unfortunately, current forms of
treatments, such as L-DOPA and cell replacement therapies, are inadequate and seem to inevitably
lead to the development of dyskinesia. We intend to undertake studies that will elucidate the
contribution of the neuroinflammatory response to neuronal degeneration, study its implication at
different stages of the disease such as early (classical symptoms) and late phases (post-treatment) of
motor deficits, and test the effects of anti-inflammatory drug therapy on functional recovery.
BASIC RESEARCH FELLOWSHIPS PROGRAM
Fellow: Jeff Biernaskie
Name of Project: Therapeutic potential of skin-derived precursor cells for cell replacement in
Parkinson's disease
Institution: Toronto Hospital for Sick Children
Amount Year One: $45,000
Amount Year Two: $45,000
Total Awarded: $90,000
Lay Summary: Work in Dr. Miller’s laboratory has demonstrated the existence of stem cells within the
adult rodent and human skin that are capable of becoming neurons, astrocytes, and oligodendrocytes
(the three main cell types in the central nervous system). This suggests that cells from one’s own skin
could potentially be used for transplantation to replace cells damaged by brain injury or disease, such
as Parkinson’s. Our first objective will seek to identify the genetic signals that “tell” these stem cells to
become neurons. Second, since Parkinson’s disease is caused by a progressive loss of neurons that
produce the neurotransmitter dopamine, parallel experiments will attempt to persuade these stem cells
to become particular types of neurons; specifically, neurons capable of restoring dopamine levels in the
brain. This project will provide important insights into the therapeutic potential of skin-derived stem cells
for Parkinson’s disease.
Fellow: Ratan Bhardwaj
Name of Project: The role of endogenous neural stem cells in mammalian adult CNS neurogenesis
towards a potential cure for Parkinson’s Disease
Institution: Karolinska Institute, Sweden
Amount Year One: $45,000
Amount Year Two: $45,000
Total Awarded: $90,000
Lay Summary: Novel recent discoveries have led us to believe that a type of adult brain cell called
neural stem cells are able to re-grow new brain cells, or that they may possess the ability to undergo
neural regeneration. Our study hopes to better understand where these neurons are located, how they
are able to grow new neurons, how to get them to go where they are needed, and how to then connect
them to the already present neurons in a functional manner. Our ultimate goal is to be able to cure
Parkinson's disease by using the patient's own stem cells to re-grow and functionally integrate their
own dopaminergic neurons into their own neuronal pathways.
Fellow: Trent Anderson
Name of Project: Cellular mechanisms of deep brain stimulation for Parkinson’s disease
Institution: University of Calgary
Amount Year One: $45,000
Amount Year Two: $45,000
Total Awarded: $90,000
Lay Summary: Surgical implantation of deep brain stimulators is the most promising new treatment for
Parkinson’s disease, reducing tremor, stiffness and slowness of movement. Whereas the clinical
benefits of DBS are well recognised, the way in which it achieves these effects is unknown. Our
research aim is to understand the mechanism of action of DBS directly at the level of individual cells
and their connections within the brain network responsible for movement. Understanding how DBS
works will provide the insight needed to improve its efficacy, direct its future application and ultimately
improve the quality of life of patients with Parkinson’s disease.
BOEHRINGER INGELHEIM CLINICAL MOVEMENT DISORDERS FELLOWSHIP
Fellow: Dr. Cindy Zadikoff
Name of Project: Clinical Studies in Parkinson's Disease
Institution: University of Toronto
Supervisor: Dr. Anthony Lang
Total Funds Awarded: $45,000 over one year.
Lay Summary: Parkinson's disease is a neurodegenerative disease that affects over 1 million people
in North America alone. Because it is slowly progressive, it has a major worldwide social and economic
impact. This grant will focus on gathering and interpreting a variety of clinical data. We will study many
aspects of PD, from risk facts, to medication side effects and response, to surgical intervention. Only
by seeing the varied expressions of PD can one ask appropriate clinical and basic science questions to
not only treat but, one day, prevent the disease.
CLINICAL RESEARCH FELLOWSHIP PROGRAM
Fellow: Connie Marras
Name of Project: Parkinson’s Disease Prognosis
Institution: University of Toronto
Amount Year One: $45,000
Amount Year Two: $45,000
Total Awarded: $90,000
Lay Summary: The progression of Parkinson’s disease varies significantly from person to person, and
the factors that determine how the disease progresses are not well understood. This work will
investigate the factors that determine or predict three important outcomes in Parkinson’s disease: time
to requiring drug treatment, quality of life and survival. Using data that has been collected by following
the course of Parkinson’s disease in 800 patients, the study will investigate the association between a
number of demographic factors, early disease symptoms and physical findings for each of these
outcomes.