2010 Research Grantees

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In 2010, PDF awarded  $1.2 million for Parkinson's disease (PD) research through its external grants program — $700,000 to support first-year studies of eight research scientists, and $500,000 to support a second year of funding for 2010 grantees who have demonstrated a successful first year of research.

The eight newly-selected grant recipients were chosen from a group of 150 applicants by a review committee that was chaired by Robert Burke, M.D., and included Stanley Fahn, M.D., PDF’s Scientific Director.

International Research Grants

Telomere Biology in Patients with Incident Parkinson’s Disease

Tobias Kurth, M.D., Sc.D., and Robert Y.L. Zee, PH.D., M.P.H.
Division of Preventive Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Total Award Amount: $82,500

The chromosomes in all cells of the body have structures on their ends called telomeres.  With time, telomeres become shorter, and shortened telomeres are associated with many diseases of aging.  Drs. Kurth and Zee will investigate whether telomere shortening is associated with Parkinson's.  Their study makes use of blood samples collected in 1997 from more than 15,000 healthy male physicians in the United States over the age of 55 as part of a clinical trial unrelated to PD.  Among this group, 353 men have developed Parkinson's.  Drs. Kurth and Zee will measure telomere length in the blood cells of these men living with Parkinson's and compare it to telomere length in the cells of study participants, matched for age, who do not have Parkinson's. In addition to seeking an association between telomere length and PD, they will study whether factors such as body mass index, smoking, and cardiovascular disease can strengthen or weaken this association.

Identification of Neuroprotective Factors in Tobacco

Leo J. Pallanck, Ph.D.
University of Washington
Seattle, Washington
Total Award Amount: $82,500

In the last decade, epidemiological studies — research that investigates the behaviors of large numbers of people in relation to disease — have suggested that people who smoke cigarettes have a lower risk of Parkinson's.  Dr. Pallanck’s goal is to identify specific chemicals in tobacco that are neuroprotective, meaning they may slow or prevent the development of PD.  In past studies he has found that tobacco extract protects neurons in fruit flies (Drosophila) genetically engineered to have characteristics of Parkinson's. He also discovered that nicotine is not a neuroprotective agent.  In new research, again using Drosophila, Dr. Pallanck will identify the chemical components in tobacco extract that are neuroprotective and characterize their chemical structures.  Because the molecular pathways of neurodegeneration in Drosophila and humans are similar, this approach may lead to a potential therapy for PD.

Potential Role of DJ-1 in Modulating the VHL/HIF Pathway and its Relevance to PD

David Park, Ph.D.*
University of Ottawa
Ottawa, Canada
Total Award Amount: $82,500

In the last decade, scientists have discovered several genes that, in rare cases, cause Parkinson's that is inherited. One of these genes is called DJ-1.  When a mutated DJ-1 gene is inherited from both parents, PD develops at a young age.  Very little is known about the mechanism by which DJ-1 contributes to the underlying progression of PD.  Dr. Park and colleagues have recently shown that DJ-1 plays an important role in protecting cells, including neurons, from stresses that can lead them to self-destruct.  In seeking to understand how DJ-1 functions, he discovered that it interacts with another protein, VHL, that also plays a key role in molecular pathways needed for the survival of neurons.  Dr. Park proposes to test the hypothesis that DJ-1 exerts its protective function through its inhibitory interaction with VHL, with experiments both in vitro and in laboratory animals.

Mechanism of FADD Recruitment and Activation in Mutant LRRK2-Induced Neurodegeneration

Hardy Rideout, Ph.D.*
Biomedical Research Foundation
Academy of Athens
Athens, Greece
Total Award Amount: $82,500

The most common genetic mutations leading to Parkinson's occur in a gene called LRRK2.  The LRRK2 gene is responsible for a protein that plays a role in signaling cells to die.  Dr. Rideout and colleagues have shown that, in neuron cells cultured in the laboratory, the LRRK2 protein must form a complex with another protein, called FADD, in order to induce cell death.  LRRK2 proteins commonly link together in two-molecule chains, and longer chains are formed when LRRK2 is mutated.  Dr. Rideout proposes that the formation of chains longer than two proteins is a critical step in the molecular pathway to cell death.  His project aims to determine how long the chains must be for them to associate more frequently with FADD, and to discover whether this association can be blocked.  He also will examine brain tissue from people whose Parkinson's developed due to LRRK2 mutations in order to better understand the connection between LRRK2 and FADD.

The Contribution of Dopaminergic System in Pathological Gambling in Parkinson’s Disease

Antonio P. Strafella, M.D., Ph.D., F.R.C.P.C.*
Centre for Addiction and Mental Health
Toronto Western Hospital/Institute
University of Toronto
Toronto, Canada
Total Award Amount: $82,500

The motor symptoms of Parkinson’s disease result from a loss of the chemical messenger dopamine in certain areas of the brain.  Drug therapies to relieve motor symptoms generally work by increasing dopamine levels, but these therapies can have side effects.  In the last five years, researchers and physicians have become more aware of people with Parkinson’s developing impulse control disorders, including compulsive gambling, after beginning dopaminergic medication.  This may happen because dopamine is involved not only in how the brain controls movement, but also in its reward system.  This study uses positron emission tomography (PET) to conduct and study brain scans of people with PD.  Dr. Strafella will use the scans to characterize abnormalities in dopamine levels in two brain areas, the striatum and the prefrontal cortex - comparing people who have developed pathological gambling with those who have not.  Newly available PET tracers used to assess dopamine levels make it possible to assess dopaminergic dysfunction more accurately and comprehensively than ever before.

LINGO1 and LINGO2 in Parkinson's Disease

Christian Wider, M.D.* and Matthew J. Farrer, Ph.D.
CHUV Lausanne and University of British Columbia
Lasusanne, Switzerland and Vancouver, British Columbia, Canada
Total Award Amount: $82,500

In recent studies, researchers have used a technique called a genome-wide association study to scan the entire genomes of several groups of people with Parkinson's.  Comparing the results to genome scans of healthy people, they discovered differences in LINGO1 and LINGO2, genes that were associated with a higher risk of PD.  Other evidence also links these genes to PD: for example, people with PD have higher activity of LINGO1 in the substantia nigra, the brain region where dopamine neurons die, leading to Parkinson's.  The first aim of this project is to do more thorough genetic studies with people with Parkinson’s to identify all the mutations that occur in these genes and find the specific changes associated with Parkinson's.  The next step will be to use mouse models of PD to study the function both of normal LINGO1 and LINGO2 and of the variations Dr. Wider identifies and links to PD.

Creating a South American Genetics Consortium on Parkinson's Disease

Cyrus Zabetian, M.D., M.S.*
VA Puget Sound Health Care System, Seattle Division
University of Washington
Seattle, WA
Total Award Amount: $82,500

Scientists have recently identified several genes that, when mutated, cause rare inherited forms of Parkinson’s disease.  However, it is becoming increasingly clear that the frequency and distribution of genetic risk factors — specific mutations in genes linked to PD — varies greatly between world populations.  Few large-scale PD genetic studies have been carried out in people from developing nations.  This goal of this project is to create a South American Genetics Consortium on PD, which will include institutions in Argentina, Brazil, Peru and Uruguay.  Dr. Zabetian aims to collect blood specimens for DNA extraction and demographic, clinical, and environmental exposure data from 1,750 people with PD and 1,650 matched controls.  The samples and data, held in a consortium coordinating center at the Seattle Institute for Biomedical and Clinical Research in Washington state, will provide a unique resource for future genetic research on PD.

Research Fellowship Grants


Ataxin-3-Mediated Regulation of Parkin Stability and Activity

Thomas Durcan, Ph.D.
Montreal Neurological Institute, McGill University
Montreal, Quebec, Canada
Total Award Amount: $45,000

Most cases of Parkinson's disease cannot be attributed directly to genetics. However, among people who develop PD at a young age, more than half have a mutation in the gene known as parkin.  One important role of the parkin protein in cells is to help label damaged cell parts for disposal during a process called ubiquitination.  Dr. Durcan's laboratory discovered that another gene, ataxin-3, can counteract parkin’s ability to participate in ubiquitination. Mutations in ataxin-3 underlie Machado-Joseph disease (MJD), and people with MJD often have Parkinsonian symptoms. This and other evidence suggests that ataxin-3 mutations may contribute to PD.  His goal is to understand the interaction between parkin and ataxin-3, and how mutations in these genes affect the normal function and stability of the parkin protein in MJD and PD.  This research is fundamental to unraveling the causes of these diseases and to identifying new treatments for them.

Correlating the Structure of Membrane-Bound Alpha-Synuclein with Function and Toxicity

Khurshida Shahidullah, Ph.D.
Joan & Sanford I. Weill College of Cornell University
New York, NY
Total Award Amount: $45,000

Parkinson’s disease is caused by the death of certain brain cells involved in controlling the body’s movements.  The cells that die contain clumps of a protein called alpha-synuclein, and mutations in the gene that produces alpha-synuclein cause inherited forms of PD.  But the details of how alpha-synuclein becomes toxic remain to be discovered. Dr. Shahidulla’s project aims to clarify how the shape of the alpha-synuclein molecule is related to its toxicity.  Depending on where it is in a cell, an alpha-synuclein molecule can assume different forms in order to carry out different tasks.  Dr. Shahidullah will use biophysical methods including fluorescence spectroscopy, CD spectroscopy, and NMR to characterize these structural changes.  An in-depth picture of alpha-synuclein’s normal conformations, in particular those that bind to membranes within cells, will shed light on how mutations disrupt both the molecule’s shape and its function. The results also may suggest forms of the protein that could serve as targets for potential PD therapies.


Targeting the CMA Pathway in Cellular Models of Alpha-Synuclein-Induced Neurodegeneration

Maria Xilouri, Ph.D.
Biomedical Research Foundation 
Academy of Athens
Athens, Greece
Total Award Amount: $45,000

The hallmark of Parkinson's is an overabundance and clumping together of the protein alpha-synuclein in certain brain cells.  These cells normally maintain a balance between the synthesis of alpha-synuclein and its disposal, which takes place through a process called chaperone-mediated autophagy (CMA).  During CMA, alpha-synuclein binds to a receptor known as Lamp2a on the membranes of the cell’s lysosomes (the waste and recycling centers).  As people age, however, Lamp2a levels decrease, and alpha-synuclein levels increase.  Dr. Xilouri's studies, in cultured cells, will investigate the relationships among levels of Lamp2a, alpha-synuclein clearance, the functioning of the lysosome and cell death.  In particular, she and her colleagues will study whether increasing the number of Lamp2a receptors, and thus enhancing CMA, clears away excess alpha-synuclein and prevents neurons from dying.  If this is the case, then Lamp2a may be a potential target for Parkinson's therapies.


The Regulation of Somatodendritic Dopamine Release

James Maas, M.D., Ph.D. 
University of California, San Francisco
San Francisco, CA
Total Award Amount: $60,000

Certain nerve cells in the brain use the chemical messenger dopamine to signal other brain cells that influence a person’s movement, balance and coordination. Usually dopamine exits a nerve cell from an area called the axon terminal and binds to receptors on the receiving cell’s dendrites.  Sometimes, however, this signaling process works in reverse — dendrites release dopamine. Little is known about what stimulates neurons to release dopamine from dendrites or the molecular mechanisms by which this occurs.  Dr. Maas' goal is to understand these processes, their roles in controlling movement and how they are disrupted in PD.  His lab has developed a technique for directly visualizing dopamine in live, cultured midbrain neurons, as it leaves the cell from the vesicles where it is stored.  He will use this technique to explore alternative hypotheses about how cells regulate the release of dopamine.


A Functional and Structural Neuroanatomic Analysis of Cognitive Impairment in Parkinson's Disease

Ryan Walsh, M.D., Ph.D.
University of Alabama at Birmingham
Birmingham, Alabama
Total Award Amount: $60,000

Ranging from mild attention difficulties to dementia, cognitive impairment is a debilitating symptom of PD.  Dr. Walsh will use fMRI (functional MRI) imaging to see how well parts of the brain communicate with each other in people with PD who have no cognitive impairment.  He will then compare these results with fMRI scans of people with PD who have cognitive impairment without dementia, and of healthy people who do not have PD.   Dr. Walsh also will compare scans taken before and after study participants have taken dopamine-based medications. Another technique, known as DTI, will provide more detailed information on the health of the bundles of neurons that directly connect far-apart brain regions.  Dr. Walsh’s research aims to identify the anatomical features underlying cognitive impairment in PD and determine whether there are differences in how people with or without cognitive impairment respond to dopaminergic medication.  The results may lead to imaging biomarkers for evaluating the nature, degree and progression of cognitive dysfunction in PD.

*Denotes second consecutive year of funding.