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Featured Research

PDF-funded Brain banks

Scientists are making inroads because thousands of people with Parkinson’s and their family members have donated their brains to science, including to PDF-supported programs at Columbia University Medical Center and Rush University Medical Center.

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PDF Grant Programs

Are you interested in furthering Parkinson's science? View PDF's open grant programs.

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2008 Research Grantees

2012 | 2011 | 2010 | 2009 | 2008 | 2007 | 2006 | 2005 | 2004 | 2003

 

In 2008, PDF awarded $900,000 to support the work of 18 scientists through its International Research Grants and Fellowships programs.

They were chosen from a group of almost 100 candidates by a scientific review committee led by Stanley Fahn, M.D., PDF’s Scientific Director.

 

Properties and adaptations of the subthalamopallidal synapse in mouse models of Parkinson’s Disease

C. Savio Chan, Ph.D.
Northwestern University 

Chicago, IL

Certain nerve cells in the brain control movement of the body’s muscles. Some of these cells normally produce a chemical messenger called dopamine, which transmits signals to a brain area called the striatum. Tremors and other motor symptoms of Parkinson’s disease develop when these dopamine neurons die. The death of dopamine neurons also affects other brain areas. In particular, nerve cells in an area next to the striatum called the globus pallidus begin sending abnormal signals that contribute to the motor symptoms of PD. In studies with mice, this project investigates how the abnormal activity is generated. Identifying and studying signaling molecules is one approach. In addition, since nerve cell communication involves electrical signals as well as chemical messengers, we are using techniques to measure the electrical current component of nerve cell communication in individual cells. Ultimately, this research may lead to new therapies to help restore normal brain signaling activity in late-stage PD.

 

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

Alessandra Chesi, Ph.D.
University of Pennsylvania
Philadelphia, PA

In the last decade, scientists have discovered several genes that, in rare cases, cause PD that is inherited. One of these genes is called PARK9. All genes are instructions contained within a cell that tell the cell how to make specific proteins. But very little is known about the normal function of the protein that the PARK9 gene encodes, much less what goes awry when it is changed, or mutated. This study aims to uncover the normal role of PARK9. Because yeast have a gene that is analogous to human PARK9, called Ypk9, yeast can be studied rather than humans. This research will define where in the cell Ypk9 functions, identify other proteins that physically associate with Ypk9, and yield information about the genes, pathways, and biological processes with which Ypk9 is involved. Basic studies of the yeast Ypk9 gene will provide clues to how human PARK9 contributes to PD and might suggest potential therapeutic strategies.

 

Role of monoubiquitylation in the translocation of α-synuclein to the mitochondria: Implications to cell toxicity and Lewy body formation in Parkinson's disease

Simone Engelender, M.D., Ph.D.
Technion-Israel Institute of Technology
Haifa, Israel

Parkinson’s disease develops when certain nerve cells die in the brain. Scientists have observed abnormal clumps of proteins in these cells. Called Lewy bodies, the clumps are made up of a protein known as α-synuclein. Although Lewy bodies are clearly related to PD, no one knows precisely how they form, or whether they cause cell death. However, studies have shown that the α-synuclein in Lewy bodies is different from normal α-synuclein: it has undergone a chemical reaction called monoubiquitylation. Previous studies have shed light on the process of monoubiquitylation and suggested that it may trigger the clumping of α-synuclein and the formation of Lewy bodies. This project will investigate how monoubiquitylation affects the function of α-synuclein, how α-synuclein concentrates in a particular location in the cell, and the potential toxicity of α-synuclein. This will yield a better understanding of how Lewy bodies form and what causes neurons to die.

 

Parkin, DJ-1 and antioxidant-deficient mouse models of PD

Matthew Goldberg, Ph.D.
University of Texas Southwestern
Medical Center
Dallas, TX

With the recent discovery of genes that cause PD when mutated, researchers have created mice with similarly defective genes in the hopes they would develop PD symptoms. The mice could then serve as test animals for potential new therapies. But the mice do not get sick--they seem to have a surplus of chemicals called antioxidants in their brains, which protect against nerve cell loss. This project proposes to overcome this obstacle by crossing mice with mutations in two genes linked to PD, known as parkin and DJ-1, with a mouse strain that lacks an important antioxidant. To determine whether the newly bred mouse strain can serve as a model for PD, the mice will be examined for Parkinson’s-like motor symptoms, and their brains will be studied for loss of dopamine-containing cells in an area called the substantia nigra.

 

Combining fast scan cyclic voltammetry and tetrode ensemble recording in a rat model of Parkinson's disease

Ledia F. Hernandez, Ph.D.
Massachusetts Institute of Technology
Cambridge, MA

Tremors and other motor symptoms of Parkinson’s disease develop when nerve cells in a brain area called the striatum do not receive enough dopamine, a chemical messenger. Very little is known about how the release of dopamine in the striatum is controlled, either in normal individuals or in people with PD. And, although the drug L-Dopa increases dopamine levels in the striatum, little is known about how it affects cells. By studying a rat model of PD in which the number of dopamine-producing cells has been reduced on one side of the brain, this project will examine the nature of dopamine release in the striatum, the effects of L-Dopa treatment in the striatum, and the potential detrimental effects of L-Dopa on parts of the striatum that already have enough dopamine. Since nerve cell communication involves electrical signals as well as chemical signals like dopamine, this study takes advantage of two electrophysiological techniques. Neural activity will be recorded with tetrodes--electrodes with four wires. And, simultaneously, fluctuations in dopamine release at the tetrode sites will be measured using voltammetry.

 

Dopaminergic modulation of synaptic transmission in the striatum

Michael Higley, M.D., Ph.D.
Harvard Medical School
Boston, MA

Dopamine is a critical chemical messenger, or neurotransmitter, which must reach cells in the brain’s striatum in order for the brain to control muscle movements normally. Parkinson’s symptoms such as tremor develop when dopamine-producing cells in the brain die, and the nerve cells in striatum receive too little of this chemical. In addition to dopamine signals, the nerve cells in the striatum receive other chemical signals, and dopamine is thought to influence how they respond to these other signals. These chemical signals travel from cell to cell across a pathway called the synapse. The goal of this work is to obtain a detailed understanding of how dopamine regulates synaptic transmission and integration in the striatum. The synapses are difficult to study with conventional methods because they are located at incredibly small protrusions of the spiny-shaped cells. Novel techniques will be used to stimulate and record synaptic activity at individual spines.

 

The potential role of neurotrophic factors in the mechanism of DJ-1-dependent astrocyte-mediated neuroprotection

David Hinkle, M.D., Ph.D.
University of Pittsburgh School of Medicine
Pittsburgh, PA

Parkinson’s disease develops when certain nerve cells, or neurons, die in the brain. Other brain cells called astrocytes surround these neurons and normally nourish and protect them. Finding ways to enhance the protective abilities of astrocytes may lead to PD therapies that slow or prevent the death of neurons. The protective abilities of astrocytes appear to depend, at least in part, on a protein called DJ-1. (In fact, people who do not have any DJ-1 protein develop a form of PD. The lack of DJ-1 protein is due to a mutation in the DJ-1 gene; this is an unusual, inherited type of PD.) Previous studies have shown that experimentally reducing the level of DJ-1 protein in astrocytes reduces their ability to protect neurons, whereas increasing the DJ-1 level enhances it. This project will begin to identify the mechanisms by which DJ-1 works, as well as other protective molecules such as growth factors. These molecules then could be targets of new anti-PD therapies.

 

BMPs define the molecular heterogeneity and function of the midbrain dopamine neurons

Milan Joksimovic, Ph.D.
Northwestern University
Chicago, IL

In the developing brain of a baby, precursor cells divide and change, and some become neurons that release the chemical messenger dopamine. It is the death of dopamine neurons that leads to PD. In the adult brain dopamine neurons are arranged in three clusters. But neurons from only one of these clusters are lost in PD. This research aims to understand how dopamine neurons diversify into three clusters during development, knowledge that may help unravel the cause of PD. Also, understanding the molecular signals that guide this process will be necessary for potential stem cell therapies--therapies that take precursor cells and coax them to develop into dopamine neurons that can then be transplanted into the brains of people with PD. One of the molecular signals important during development is called bone morphogenetic protein (BMP). These studies examine the role of BMP in the formation of the different clusters of dopamine neurons.

 

Intrabodies as potential therapeutics against Parkinson's Disease pathology

Sandra Lynch, Ph.D., M.Sc., M.B.A.
Wadsworth Center, New York State
Department of Health
Albany, NY

Parkinson’s disease develops when certain nerve cells die in the brain. Scientists have observed abnormal clumps of proteins, called Lewy bodies, in these cells. Lewy bodies are made up of a protein known as α-synuclein. Scientists are unsure what role α-synuclein and Lewy bodies play in the death of cells. But preventing the formation of Lewy bodies could have therapeutic value. This research explores the potential of molecules known as intrabodies, a variant of the body’s disease-fighting antibodies, to prevent the clumping of α-synuclein, and the formation of Lewy bodies. The goal of this study is to engineer potent intrabodies that interact with α-synuclein, making it more soluble and stable within cells in culture. If successful, intrabodies can then be tested in animal models of PD. Other recent studies have shown that intrabodies can inhibit the clumping, or aggregation, of α-synuclein as well as its toxicity.

 

Aging, toxic damage and alpha-synuclein pathology in the primate brain

Alison McCormack, Ph.D.
The Parkinson’s Institute and 
Clinical Center
Sunnyvale, CA

Lewy bodies, clumps of protein found in brain cells affected by PD, are considered a hallmark of the disease. Yet the relationship of Lewy bodies to the cause of PD remains unclear. It is known that the key component of Lewy bodies is a protein called α-synuclein. In studies with monkeys, this project will investigate whether aging and exposures to toxins lead to a pattern of Lewy body formation similar to PD in humans. Additional goals are to learn about the mechanisms leading α-synuclein to assemble into Lewy bodies, and to discover whether increased levels of α-synuclein result in more Lewy body formation. If so, then decreasing α-synuclein levels may be a strategy for PD therapy.

 

The role of mitochondrial oxidative phosphorylation defects in Parkinson's Disease

Carlos Moraes, Ph.D.
University of Miami
Miami, FL

Every cell in the body contains mitochondria--substructures, considered the cell’s powerhouses, that take nutrients and convert them into chemical fuel. Scientific evidence has long linked problems at the mitochondria with PD. In particular, research has pointed to a defect in an area of the mitochondria called complex I in the cells of people with PD. This study compares defects in two mitochondrial areas, complex I and complex IV, to find out whether the involvement of complex I is specific to PD. Genetically modified mice will be created with a defect either in complex I or in complex IV of mitochondria in cells of a brain area called the substantia nigra. This area of the brain contains the nerve cells affected by PD. Results will show whether cells in the substantia nigra are more sensitive to defects in complex I than to defects in complex IV.

 

PON2 as a target of DJ1 in a model of Parkinson’s Disease

David Park, Ph.D.
Ottawa Health Research Institute
Ottawa, Canada

Parkinson’s disease develops when certain cells, or neurons, die in the brain. Scientists have recently identified several genes that, when mutated, cause rare inherited forms of the disease. One of these genes is called DJ-1. How a malfunction in DJ-1 could lead to cell death and PD is not well understood. Previous studies suggest that DJ-1 plays a protective role--it may shield cells from damage and death under conditions of oxidative stress, a build-up of molecules that initiate damaging oxidation reactions within the cell. In addition, the protein PON2--an antioxidant--physically interacts with DJ-1. This project will investigate whether DJ-1 regulates PON2 activity, a potential means by which DJ-1 may protect the cell from oxidative damage. The results will improve understanding of the role of DJ-1 in PD, and map out, at the molecular level, some of the steps that lead to cell death in PD.

 

Role of HtrA2/Omi dysfunction in Parkinson’s Disease

Jean-Christophe Rochet, Ph.D.
Purdue University
West Lafayette, IN

Parkinson’s disease develops when certain cells, or neurons, die in the brain. The surviving cells are often damaged by so-called oxidative stress--injury caused by molecules called free radicals inside the cell. The protein known as DJ-1 is thought to protect cells from oxidative stress. And another protein, HtrA2, can either have a protective effect or cause the cell to die, depending on its form. This project investigates the role of HtrA2 and its interaction with DJ-1. One goal is to determine whether decreasing the amount of protective HtrA2 in the cell makes it more sensitive to oxidative stress. Then the potential for DJ-1 to counteract the effect of the deadly form of HtrA2 will be studied. Understanding these molecular pathways related to cell death may suggest new strategies for PD therapies.

 

Pharmacological inhibition of nuclear factor - kappa B in a mouse model of Parkinson's Disease

Shaji Theodore, Ph.D.
University of Alabama-Birmingham
Birmingham, AL

A chemical messenger called dopamine normally helps the brain communicate with muscles so that they move smoothly and in a coordinated way. When there is not enough dopamine in a brain area called the striatum, motor symptoms of Parkinson’s, such as tremor, develop. In addition, other changes take place in the striatum. The nerve cells there develop high levels of a potentially toxic protein called α-synuclein. And immune system cells inflame the striatum, and injure nerve cells. This project investigates: first, whether excess α-synuclein triggers inflammation and nerve cell damage in the striatum in mice; and second, whether blocking nuclear factor ĸB, another molecule important in setting off inflammation, can slow or stop this process. If so, this would support a new strategy for protecting nerve cells from damage and death in PD.

 

Role of axonal protein synthesis for the normal function of the dopaminergic axon

Enrique Torre, Ph.D.
Emory University School of Medicine
Atlanta, GA

In the brain, nerve cells in an area called the substantia nigra produce the chemical messenger dopamine, which helps the brain coordinate the movement of muscles. These neurons extend long thread-like projections to another area called the striatum, where the dopamine is released. Motor symptoms of PD such as tremor develop when these cells die, and striatum cells do not receive enough dopamine. It has been proposed that the processes leading to cell death begin inside the thread-like projection, or axon, of the cell. Normally, the cell makes proteins within the axon that help it to grow and survive. Molecules known as mRNAs direct the synthesis of these proteins. This project investigates, in mice, whether a lack of mRNAs contributes to cell death. The mRNAs normally present in the axons of dopamine neurons will be identified, and their levels and locations in both normal and diseased axons will be compared.

 

Identification of a novel gene for Parkinson’s Disease

Carles Vilariño-Güell, Ph.D.
Mayo Clinic Jacksonville
Jacksonville, FL

Most people with PD do not have a relative with the disease. But in a very few families, several people are affected by PD, and the disease is inherited. In an effort to identify a new gene for PD, this project focuses on two large families from North America, both with strong histories of PD as well as other, related, neurological disorders. Affected family members often have a specific mutation in a gene called LRRK2, which is linked to PD--but are diagnosed with a different disease. This suggests a mutation in a different, unknown, gene is causing PD. To identify this gene, DNA samples from all family members willing to participate will be analyzed to discover a unique region inherited by those with a neurological disease but not by healthy individuals. Further refining the analysis will lead to identification of the PD gene and its mutation.

 

Modifiers of PINK1-dependent neurodegeneration using a Drosophila Parkinson's Disease model

Georg Vogler, Ph.D.
Burnham Institute for Medical Research
La Jolla, CA

PD develops when brain cells known as dopamine neurons die. A molecule called PINK 1 plays an important role in protecting these cells, and mutations in the PINK 1 gene are associated with PD in humans. Experiments with fruit flies (Drosophila melanogaster) have shown that dopamine neurons die in flies with reduced levels of PINK 1. The reduction in PINK 1 also has another effect on fruit flies, much more easy to observe: their eyes develop dark spots or patches, because certain eye cells also die. This study takes advantage of this effect. Strains of fruit flies will be bred, each missing specific gene. If their eyes develop spots, this suggests that the missing gene may also play a role in dopamine neuron death, and may merit further investigation for its relationship to PD. Genes that are known to be linked to PD and to molecular pathways related to PD also will be tested.

 

Neuroprotective effects of phenylbutyrate in the mutant human α-synuclein transgenic mouse model

Wenbo Zhou, Ph.D.
University of Colorado-Denver
Denver, CO

The motor symptoms of PD begin when certain nerve cells in the brain die. A protein called DJ-1 is known to protect these dopamine neurons, maintaining their health and preventing cell death. This project will test whether a recently discovered drug called phenylbutyrate can increase DJ-1 levels and protect nerve cells from death in a new mouse model of PD. In previous studies phenylbutyrate was shown to protect dopamine neurons in a culture dish from death after toxic treatments. The drug also has been tested successfully in mice that have PD symptoms because of a sudden loss of dopamine neurons, brought about by a toxic chemical. The new research evaluates the drug in a mouse model, developed in this laboratory, in which the death of dopamine neurons is slow and progressive, like that in humans with PD.