Parkinson Society Canada
National Research Program Awards
for 2004-2006 Cycle
Granting period
July 1, 2004 – June 30, 2006
Pilot Project Program Grants
M&M Pilot Project Grant
Researcher:Abbas F. SadikotName of Project: Pitx3: A novel transcription factor crucial to survival of midbrain dopaminergic subpopulations
Institution:Montreal Neurological InstituteAmount Year One: $45,000
Lay Summary: We have recently discovered a protein (Pitx3) expressed exclusively by midbrain dopaminergic neurons, a group of cells that are lost in Parkinson’s disease. Our studies indicate that a mouse (Aphakia) that does not produce Pitx3 has premature death of dopamine neurons and behavioural deficits that resemble Parkinson’s disease. We therefore believe that Pitx3 is essential to the survival of dopamine cells, and its production may be compromised in Parkinson’s disease, leading to the observed loss dopamine producing nerve cells. We will first determine the precise location of Pitx3 in normal rodent dopamine nerve cells. We will also determine the Pitx3 content of dopamine neurons in autopsy brains obtained from patients with early or late Parkinson’s disease. Finally, we will look at dopamine cells in a cell culture dish, and determine whether Pitx3 expression protects them from cell death following exposure to toxins. The discovery of a new genetic pathway specifically localized to those dopamine cells most likely to degenerate, would suggest an important research avenue into new treatments aimed at rescuing vulnerable subpopulations in Parkinson’s disease.
Friedman Pilot Project Grant
Researcher:Brian E. Staveley
Name of Project: The role of parkin and ubiquitin carboxy-terminal hydrolases in Drosophila models of Parkinson's disease
Institution:Memorial University of Newfoundland
Amount Year One: $45,000
Amount Year Two: n/a – one year grant
Total Awarded:$45,000
Lay Summary:Defects in a number of genes have been linked to inherited forms of Parkinson's disease. Many of these genes are involved in the extremely important process of destroying unwanted, defective or toxic proteins. This basic fundamental biological mechanism is common to humans and a wide range of well-known model organisms including mice and fruit flies. Using the well-established fruit fly model of Parkinson's disease, we can examine the essential biological functions disrupted in this disease. Recently, our laboratory has demonstrated that increasing the activity of a gene, named parkin, which is responsible for targeting harmful proteins to destruction, can reverse Parkinson's disease-like symptoms in fruit flies. In our pilot study, we wish to explore three related avenues of investigation. We intend to test the ability of parkin to reverse Parkinson's disease-like symptoms under various conditions. We will evaluate the consequences of decreasing the activity of the parkin gene in neurons. In addition, we will study the effects of increasing and decreasing the activity of uch, another gene that is linked to Parkinson's disease and is involved in protein degradation. We believe that this pilot project will provide the basis for an extremely informative research program.
Researcher:Howard T. J. MountName of Project: Energetic charge and monoamine turnover in novel lines of α-synuclein-transgenic mice
Institution:University of Toronto Centre for Research in Neurodegenerative Diseases
Amount Year One: $45,000
Amount Year Two: n/a – one year grant
Total Awarded:$45,000
Lay Summary: Overabundance and/or mutations in the alpha-synuclein (a-SYN) gene cause familial Parkinson's disease (PD). Mice engineered to produce human forms of a-SYN exhibit the sticky protein deposits of aggregated a-SYN seen in PD brains. However, the mechanism by which a-SYN accumulation leads to brain cell death remains obscure. We hypothesize that a-SYN causes impaired cellular energy homeostasis. Energetic failure is implicated in the cell death associated with PD and inhibiting cellular energy generation has been found to promote a-SYN aggregation. It remains unclear whether a-SYN might in turn influence cellular energy homeostasis. We will test whether a feedback relationship exists between human a-SYN expression and depletion of cellular energy stores, in three new lines of normal and mutant human a-SYN-producing mice recently developed at the CRND. We will first examine our new mice behaviourally for PD-like symptoms. Thereafter, we will use a magnetron to stabilize energy molecules throughout the brain, so that we can measure their levels in a regionally specific manner. In the same brain areas, we will examine the turnover of PD-affected neurotransmitters (eg dopamine), to ascertain how closely neurochemical deficits in our mice recapitulate the human disease.
Researcher:David ParkName of Project: Use of RAG mice to delineate involvement of the adaptive immune response in Parkinson’s disease
Institution:University of Ottawa Neuroscience Research Institute
Amount Year One: $45,000
Amount Year Two: n/a – one year grant
Total Awarded:$45,000
Lay Summary:Parkinson's disease (PD) is characterized by loss of specific brain cells which secrete an important factor, dopamine, important for control of movement. The mechanism by which this loss occurs in PD is not completely understood. We will test a relatively novel hypothesis that a harmful immune response plays a critical role in this dysfunction. In an animal model of PD, we will determine whether elimination of this potentially harmful immune response leads to preservation of dopamine brain cells.
Researcher:Scott Heximer and Hubert Van TolName of Project: Defining the role of RGS2 as a modulator of dopamine signalling in the striatum
Institution:University of Toronto
Amount Year One: $45,000
Amount Year Two: n/a – one year grant
Total Awarded:$45,000
Lay Summary: The central area of the brain, called the striatum, integrates information about the body’s posture, position, and balance, to help coordinate proper muscle control. The striatum works in close communication with another brain region, the substantia nigra, so that together they can send balance/coordination and movement commands to the muscles. Communication between these two brain regions occurs via chemical messengers called neurotransmitters. Dopamine is an especially important messenger produced in the substantia nigra. Proper release of dopamine messages from the substantia nigra helps the striatum coordinate muscle movements. Interference with normal dopamine communication pathways can, therefore, result in serious motor control defects. In Parkinson’s Disease there are fewer dopamine-producing cells in the substantia nigra, resulting in disruption of normal communication with the striatum and a corresponding loss of coordinated movement. We are interested in understanding how normal dopamine signaling is controlled in the striatum so that we might develop novel treatment strategies to restore normal striatal function in Parkinson’s patients. Specifically, we have identified a gene in the mouse striatum that appears to recognize the signs of abnormal dopamine communication and has the potential to restore proper communication. We propose to use genetically altered mice in which this gene has been ablated in order to study its function as a regulator of striatal function.
New Investigator Award Program
Heard New Investigator Grant
Researcher:Oury Monchi
Name of Project:Cognitive deficits in Parkinson’s disease: functional neuroimaging
Institution:Institut Universitaire de Geriatrie de Montreal
Amount Year One: $45,000
Amount Year Two: $45,000
Total Awarded:$90,000
Lay Summary:Parkinson’s disease (PD) is characterized by tremor, slowness of movement, and difficulty with balance. However, deficits in executive functions are also present in patients with the disease. These functions can be characterized as the cognitive processes required to plan or alter behaviour in a changing environment. The neurobilogical dysfunctions responsible for these cognitive deficits in PD are not well understood. In this project we will use new functional brain imaging techniques to compare the physiological and anatomical dysfunctions responsible for the cognitive deficits observed in PD with those responsible for the motor deficits. Two functional magnetic resonance imaging studies are proposed that will take place on PD patients at the early stages of the disease and matched controls. Gaining a greater understanding of the origins of cognitive deficits at the early stages of the disease will help us predict how these can sometimes result in dementia at the later stages. This knowledge should improve clinical management of patients with PD in the longrun.
Researcher:Elena Moro
Name of Project: Motor Cortex Stimulation for Parkinson’s disease: understanding possible mechanisms of action through neuroimaging
Institution:TorontoWesternHospital
Amount Year One: $45,000
Amount Year Two: $45,000
Total Awarded: $90,000
Lay Summary: Chronic Motor Cortical Stimulation (MCS) has been initially used for pain and recently applied to movement disorders. A clinical improvement on parkinsonian signs has been reported in some Parkinson’s disease (PD) patients. These findings need to be confirmed with larger studies. Moreover, the mechanism of action of MCS in PD has never been investigated. Transcranial magnetic stimulation, a neurophysiological technique similar to CMS, can activate cortical motor areas and ameliorate bradykinesia and rigidity and has been recently found to be able to induce striatal dopamine release. We propose to evaluate the clinical effects of CMS in 12 PD patients. Once the electrical parameters of stimulation are fully investigated to achieve the maximal benefit, they will undergo a PET with [11C] raclopride to investigate dopamine release in the striatum. During the second year of the study, they will be studied with [15O]H2O PET to investigate changes in regional cerebral blood. This will be the first clinical study with CMS for PD in Canada. MCS is a much simpler, potentially safer and less expensive surgical option then deep brain stimulation. A full investigation of CMS will allow a determination of its efficacy and provide insight into its mechanism of action.
Researcher: Frédéric Calon
Name of Project:Nanotechnology approach towards brain delivery of neurotrophic factors in Parkinson's disease
Institution:LavalUniversityMedicalCenter (CHUL)
Amount Year One: $45,000
Amount Year Two: $45,000
Total Awarded: $90,000
Lay Summary: Several potentially therapeutic drugs are not available for patients suffering from brain diseases because they do not cross the blood-brain barrier (BBB). Glial-derived neurotrophic factor (GDNF) is a promising drug candidate for Parkinson's disease (PD) treatment. This molecule has been consistently shown to be effective to slow down or reverse the neurodegeneration of dopaminergic cells; the death of these cells being the cause of PD. Because GDNF does not cross the BBB, it can only be given to PD patients through holes drilled into their skull. It seems unlikely that such invasive methodologies can be applied on a large scale in human patients. Here, we propose to encapsulate GDNF or a gene expressing GDNF into small lipid nanocontainers called liposomes. We will conjugate these liposomes with vectors that cross the BBB. After intravenous injections in animals, we expect the GDNF-liposome-vector formulation to be ferried into brain cells and to increase brain concentrations of GDNF. We will then assess the neuroprotective and neuroregenerative properties of our GDNF formulation in a mouse model of PD. If successful, the results of this project would strongly suggest that large drug molecules, such as GDNF, could be used in the treatment of PD.
Researcher:Alex Rajput
Name of Project: Alpha-synuclein genetics in pathologically verified Parkinson’s disease
Institution:RoyalUniversityHospital (Saskatoon)
Amount Year One: $45,000
Amount Year Two: $0
Total Awarded: $45,000
Lay Summary: Parkinson’s disease (PD) causes slowness, stiffness, and resting tremor. The lifetime risk for developing PD in Canada is estimated at 4%. PD is caused by loss of cells in part of the brain called the substantia nigra. There is increasing evidence that genetics make a person vulnerable to environmental factors which trigger the disease. The process in the brain progresses slowly over approximately 5 to 10 years. When enough cells have died, the patient begins to have symptoms. Lewy bodies are inclusions found at autopsy in the substantia nigra brain cells in PD. A major part of LB is a-synuclein protein. Mutations in the gene for this protein have been reported in rare families with dominantly inherited PD (i.e. parent has a 50:50 chance of passing on the disease to child). The promoter region of the a-synuclein gene determines how active the gene is. Markers in this region are associated with patients clinically diagnosed with PD. We will investigate the role of the promoter region of the a-synuclein gene in autopsy-verified PD cases. At present, there is no cure for PD, nor can we slow its progression. Identifying those at risk for developing PD could allow early treatment.
Researcher:Susan H. Fox
Name of Project: Alpha Investigation of the neural mechanisms underlying psychosis in Parkinson’s disease
Institution: Toronto Western Hospital
Amount Year One: $45,000
Amount Year Two: $0
Total Awarded: $45,000
Lay Summary: Patients with Parkinson’s disease (PD) can often be affected by problems with psychiatric symptoms such as confusion, delusions and hallucinations. Unfortunately treatments for such psychosis are limited. Reducing the medication used to treat the PD or using agents that block the brain chemical, dopamine can help reduce psychosis but often only at the expense of worsening parkinsonian motor symptoms. At present, the brain mechanisms responsible for these psychotic problems are unknown. The aim of this project is to develop a better understanding of the pathways involved in causing psychosis in PD. To this end, we will develop an animal model of psychosis in PD using the MPTP primate. We will then assess changes in brain function, to determine the pathways involved. This work will be extended to patients with PD and post mortem tissue from patients with PD and psychosis. This will enable us to identify potential treatments for psychosis that will reduce psychosis without worsening PD.
Basic Research Fellowships Program
Fellow:John R. Adams
Name of Project: Therapeutic Neuroimaging investigation of early biomarkers for nigrostriatal cell damage in patients with a high genetic risk of developing Parkinson’s disease
Institution:Pacific Parkinson’s Research Centre, University of British Columbia
Amount Year One: $45,000
Amount Year Two: N/a
Total Awarded:$45,000
Lay Summary:Symptoms of Parkinson’s disease (PD) typically develop after a loss of approximately 80% of dopamine producing cells within the substantia nigra. Ideally, the degeneration of these cells would be halted prior to the development of symptoms. In order to develop therapies to arrest cell death, markers of early dopamine cell loss at a pre-symptomatic stage are required. Functional imaging with positron-emission tomography (PET) provides a non-invasive means of investigating biochemical changes within the brain. The PET findings for established PD have been well documented but the earliest changes remain unknown. In this study we propose to use PET and 3 different radioactive compounds to study at-risk, asymptomatic members of families with inherited PD and determine the earliest biochemical changes associated with damage to dopaminergic nerve cells. By identifying the earliest changes we will be able to study the process by which symptoms develop, understand how the biochemical abnormalities change over time and ultimately provide information for the development of therapeutic agents to prevent further cell death and the appearance of symptoms.
Fellow:Anna MoszczynskaName of Project: Parkin, alpha-synuclein, and dopamine transporter interactions: Implications for Parkinson’s disease
Institution:Centre for Addiction and Mental Health (Toronto)
Amount Year One: $47,500
Total Awarded:$47,500
Lay Summary: PD involves injury to nigrostriatal DAergic system and one of Daergic system components is DAT. Also, alpha-synuclein and parkin has been implicated in PD. The involvement of these three proteins in PD implicates the importance of their interaction. DAT can be regulated via several mechanisms, one of them being direct interaction with other proteins. So, there is a possibility of such interaction between alpha-synuclein, parkin, and human DAT (hDAT). We have already demonstrated that alpha-synuclein increases hDAT function through direct protein-protein interaction. Enhanced hDAT activity may facilitate increased production of reactive oxygen species via increased intracellular DA concentration. My preliminary data showed that (1) parkin blocks alpha-synuclein-induced upregulation of hDAT and (2) parkin forms complex with DAT in striatal tissue. These results have led to my hypothesis that the protein-protein interaction between parkin and hDAT may be responsible for the observed functional modulation of hDAT. Since action of parkin protects against alpha-synuclein-induced increase in intracellular DA content, elucidation of nature of interactions between alpha-synuclein, parkin, and DAT may provide insight into the etiology of Parkinson's disease and suggest novel therapeutic strategies for its treatment.
Fellow:Joohyung Lee
Name of Project:Role of abnormal synaptic plasticity in levodopa-induced dyskinesia in Parkinson’s disease
Institution:TorontoWesternHospital
Amount Year One: $42,750
Amount Year Two: $47,500
Total Awarded:$90,250
LaySummary:The main limitation for Parkinson’s disease is the emergence of treatment related unwanted movements, several years after starting therapy. These unwanted movements are known as dyskinesias. We believe that these dyskinesias result from the brain learning abnormal motor patterns following chronic treatment. If we can reverse or prevent this learning detrimental learning process, we can reduce the problem of dyskinesia in Parkinson’s disease. The project will assess the potential of 3 experimental treatments to achieve this aim.
Fellow:Katerina Venderova
Name of Project:Role of the endocannabinoid system in Parkinson’s disease and levodopa-induced dyskinesia
Institution:Toronto Western Research Institute
Amount Year One: $38,000
Amount Year Two: $42,750
Total Awarded:$80,750
LaySummary:Recently, a new group of receptors and their neuromediators, termed the endocannabinnoid system, was identified and found to be abundantly represented in areas responsible for generation of the symptoms of Parkinson’s disease (PD). Our group was the first to show marked changes in this system in PD. Based on our previous experiments we hypothesize that these changes are important in the development of PD and also play an important role in development of levodopa-induced dyskinesia (LID), the major side effect of current treatment. The goals of our research are to increase the understanding of the role of endocannabinoids in PD and LID and ultimately find novel treatments for PD and/or LID.