2009 Research Grantees

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In 2009, PDF awarded a series of grants amounting to $1.4 million to support the work of 12 research scientists, through two of its larger research programs: the International Research Grants Program (IRGP) and the Postdoctoral Research Fellowship Program. 

The grant recipients were chosen from a group of nearly 160 applicants by a scientific review committee led by Stanley Fahn, M.D., PDF’s Scientific Director. 

International Research Grants

PD4PD: Partnered Dance for Parkinson Disease

Gammon Earhart, Ph.D., P.T.
Washington University School of Medicine
St. Louis, MO
Total Award Amount: $82,500

For people with Parkinson’s exercise is widely recognized as helping to maintain mobility and improve secondary symptoms such as depression.  But most studies have evaluated only the short-term effects of exercise, and have not addressed whether exercise can modify the progression of PD.  This study will investigate both the short and long-term effects of participation in a community based dance program for people with PD.  Dance is a socially engaging and motivating form of exercise that directly addresses needs of people with PD, including cueing, cognitive strategies, balance exercise and aerobic conditioning.  Participants in a control group will receive no intervention.  We will evaluate how the dance exercise program impacts the symptoms of PD, how performance on standard clinical measures of physical function may change over time with disease progression in the absence of an exercise intervention and whether exercise may modify disease progression.

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 PD 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.  We have recently shown 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, we discovered it interacts with another protein, VHL, that also plays a key role in molecular pathways needed for the survival of neurons.  We propose 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 PD occur in a gene called LRRK2.  The LRRK2 gene is responsible for a protein that plays a role in signaling cells to die.  We 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.  We also know that LRRK2 proteins commonly link together in two-molecule chains, and longer chains are formed when LRRK2 is mutated.  We propose that the formation of chains longer than two proteins is a critical step in the molecular pathway to cell death.  Our 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.  We also will examine brain tissue from people whose PD was 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 Strafella, M.D., Ph.D.
Centre for Addiction and Mental Health
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 brain scans with positron emission tomography (PET) of people with PD 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.

PGI2 mediated activation of PPARs: Implications for Parkinson’s Disease

Peter Teismann, Ph.D.*
University of Aberdeen
Aberdeen, Scotland
Total Award Amount: $82,500

Parkinson’s disease develops when brain cells known as dopamine neurons die.  This study contributes to the understanding of the molecular mechanisms underlying this cell death.  In studies of mice with PD symptoms induced by the chemical MPTP, we found that cyclooxygenase (COX)-2, known for its role in inflammation, is instrumental in neurodegeneration in PD. One pathway by which COX-2 works involves a prostaglandin called PGI2. PGI2 can activate peroxisome proliferator activated receptors (PPARs).  One of these PPARs can induce apoptosis—a kind of cell suicide—as well as inhibit the protective effect of another PPAR.  This project investigates the function and mechanisms of PGI2 in the neurodegenerative process.  In addition to studies in the mouse MPTP model, we will measure PGI2 levels and PPAR expression in brain tissue from people with PD.  The aim of this study is to understand of the roles of COX-2, PGI2, and PPARs in the progression of PD.

LINGO1 and LINGO2 in Parkinson's disease

Christian Wider, M.D.
Mayo Clinic
Jacksonville, FL
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 PD.  Comparing the results to genome scans of control subjects, they discovered differences in the genes coding for two proteins--LINGO1 and LINGO2--that were associated with a higher risk of PD.  Other evidence also links these genes to PD: for example, people with PD have higher levels of LINGO1 protein in the substantia nigra, the brain region where dopamine neurons die, leading to PD.  The first aim of our project is to do more thorough genetic studies with people with Parkinson’s to identify all the mutations that occur in these proteins and find the specific changes associated with PD.  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 we identify and link to PD.

Creating a South American genetics consortium on Parkinson's disease

Cyrus Zabetian, M.D., M.S.*
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.  We aim 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.


Postdoctoral Research Fellowships

Basic Science

Investigating the function of the Parkinson's disease gene ATP13A2/PARK9

Alessandra Chesi, Ph.D.*
University of Pennsylvania School of Medicine
Philadelphia, PA
Total Award Amount: $50,000

Scientists recently have discovered several genes that, in rare cases, cause PD that is inherited.  One of these genes is called PARK9. Because yeast have a gene that is analogous to human PARK9, called YPK9, yeast can be studied rather than humans.  Last year we discovered that the YPK9 protein neutralizes the toxicity of another protein—alpha-synuclein—that builds up to toxic levels in the dopamine neurons of people with Parkinson’s.  YPK9 also helped protect cells from environmental exposure to the metal manganese.  In humans, manganese exposure is linked to a PD-like syndrome.  New research will investigate the mechanism for this protection.  We will begin our studies in yeast and then expand the work to mammalian cells, to find out whether the human PARK9 protein functions in the same way as the yeast protein.  These studies will shed light on the interaction between genetic and environmental risk factors for PD.

Novel therapeutic approaches to alpha-synuclein induced Parkinson’s disease

Navneet Ammal Kaidery, Ph.D.
Weill Medical College of Cornell University 
New York, NY
Total Award Amount: $50,000

Parkinson’s disease develops when certain nerve cells die in the brain.  Scientists have observed abnormal clumps of a protein called alpha-synuclein in these cells. Such abnormal alpha-synuclein is related to cell death in PD.  Our research will test, in mice, the effectiveness of a synthetic chemical compound in protecting dopamine neurons from alpha-synuclein toxicity.  The compound, a synthetic triterpenoid known as TP-319 EA, activates a signaling pathway that is known to protect cells from oxidative damage and inflammation.  These two processes lead to cell death and have been linked to PD.  In addition, impairment of this pathway, called the Nrf2/ARE pathway, has been implicated as a cause of PD.  In these studies, we will give oral doses of TP-319 EA to mice that have Parkinsonian symptoms induced by the drug MPTP and study this new compound’s ability to protect dopamine neurons.

Deficits in formation and maintenance of habits in preclinical Parkinson's disease

Stefan Sandberg, Ph.D.
University of Washington 
Seattle, WA
Total Award Amount: $50,000

Certain nerve cells in the brain control movement of the body’s muscles.  Some of these cells normally produce a chemical messenger called dopamine.  Tremors and other motor symptoms of Parkinson’s disease develop when a critical number of these dopamine neurons die.  Even sooner, however, changes in dopamine signaling can disrupt the circuitry between different brain regions in ways that lead to cognitive symptoms—memory disturbances, for example—and difficulties in maintaining focus or dividing attention between tasks.  Certain learning difficulties have been associated, in an animal model, with a decrease in so-called phasic dopaminergic signaling.  This study aims to understand the changes in brain neurochemistry in an animal model with a deficit in phasic dopaminergic signaling.  Among other experiments, dopamine release will be monitored using implanted electrodes as the animals respond to the unexpected receipt of a food pellet.  The results will shed light on the neurochemical processes underlying cognitive changes in PD.

The role of lipid phosphorylation in vesicular monoamine transport

Pedro Soldado, Ph.D.
University of California, San Francisco
San Francisco, CA
Total Award Amount: $50,000

Dopamine is a chemical messenger released by certain nerve cells in the brain that help control movement of the body’s muscles.  Before being released by cells, dopamine is stored in small compartments called vesicles.  A molecule called the vesicular monoamine transporter helps nerve cells store dopamine and other neurotransmitters inside these vesicle compartments—an important factor for normal nerve cell function.  The vesicular monoamine transporter also appears to play an important role in protecting cells against toxins, from both within and without.  Changes in the transporter’s protective ability may play a part in PD, which develops when dopamine neurons die.  None of these processes are well understood.  In recent studies using artificial membranes we have discovered a molecule found within cells, PIP2, that inhibits the function of a vesicular monoamine transporter called VMAT2.  Our new project will characterize the interaction between PIP2 and VMAT2 at the molecular level.

Clinical Research

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, AL
Total Award Amount: $60,000

Parkinson’s disease is diagnosed by motor symptoms such as tremor and rigidity. But cognitive dysfunction—ranging from attention difficulties, for example, to dementia—is also a debilitating component of PD.  Scientists do not have a good understanding of which brain networks are involved in cognitive dysfunction in PD, which networks are sensitive to dopamine, and whether the areas affected are different in early and late-stage disease.  This study investigates the neuroanatomy underlying the progression of cognitive impairment in people with PD using so-called resting-state networks (RSNs), which measure the health of connections between brain regions by looking at how parts of the brain function using a form of magnetic resonance imaging called fMRI.  We also will assess the effect of treatment with dopamine.  Another technique using MRI, probabilistic tractography (DTT), gauges the health of anatomical connections between brain regions, specifically white matter tracts.  When combined, studies with RSNs and DTT could point to biomarkers for understanding cognitive changes in PD.

*Indicates scientist previously funded by PDF