2011 Investigator-Initiated Projects

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Among PDF's research awards of $5.5 million in 2011, we awarded $1 million for 11 novel investigator-initiated research projects designed to understand the cause(s) of and find a cure for Parkinson’s disease. 

Abstracts of these projects appear below. They ranged from basic science investigations of the cellular mechanisms that underlie the disease, to studies of potential new therapies. They also included ideas that may lead to symptomatic relief for the people who are living with Parkinson’s today.

The projects are funded through two key programs: the International Research Grants program and the Research Fellowships program, which both seek to encourage novel ideas by respectively funding “high-risk/high-reward” projects and supporting scientists in the early stages of their careers.

International Research Grants

Evaluating the Role of Mitochondrial Dynamics in Parkinson’s Disease in an In Vivo Vertebrate Model: Real-Time Live Imaging of Mitochondrial Dynamics in Dopamine Neurons in Whole Zebrafish

Sarah B. Berman, M.D., Ph.D., and Edward Burton, M.D., D.Phil.
University of Pittsburgh
Pittsburgh, PA
Total Award Amount: $165,000 over two years

Mitochondria are energy-producing structures found inside all cells of the body. Many studies have shown that mitochondria are damaged early in Parkinson’s disease. Drs. Berman and Burton have developed methods to study mitochondria in dopamine neurons — the cell type affected by Parkinson’s — in live zebrafish. Zebrafish are the fish equivalent of the lab mouse, yet are also transparent early in life. Using genetic tools to make the mitochondria in zebrafish fluorescent, the researchers will be able to record images of individual mitochondria as they move within the axons of dopamine neurons — a feat that has proven very difficult in the past. They will first examine mitochondrial movements in normal zebrafish, and then compare these to zebrafish with mutations in alpha-synuclein (a gene implicated in Parkinson’s), as well as zebrafish exposed to mitochondrial toxins. The researchers also will engineer zebrafish in which certain mitochondrial proteins can be tracked over a long period of time, and in which potential Parkinson’s therapies aimed at protecting mitochondria could be screened.

Impact of Low- and High-Frequency Electrical Stimulation on the Inputs, Integrative Properties and Output of the Subthalamic Nucleus

Mark D. Bevan, Ph.D.
Northwestern University
Evanston, IL
Total Award Amount: $165,000 over two years

Nerve cells communicate by both chemical and electrical signals. In people with Parkinson’s disease, the loss of dopamine, a chemical signaling molecule, leads to overactive electrical signaling in an area of the brain called the subthalamic nucleus (STN).One therapy for Parkinson’s — deep brain stimulation (DBS) — delivers an electric current to the STN and helps restore normal patterns of signaling. But how this works at the level of individual nerve cells and their connections is still not well understood. In laboratory studies, Dr. Bevan will use slices of brain tissue from mice that have dopamine loss and Parkinson’s symptoms. Then he will use electrophysiological techniques to study patterns of electrical signaling of STN neurons in the brain slices. He will compare the effects of low- and high-frequency stimulation on the STN and try to determine how the stimulation actually restores normal function. A better understanding of the mechanisms underlying brain stimulation may lead to refinements in DBS therapy or to drug or gene therapies that mimic its effects.

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.
Brigham and Women’s Hospital
Boston, Massachusetts, MA
Total Award Amount: $165,000 over two years

DNA, the map of life, is really like a map—neatly folded and organized into structures called chromosomes that are found in all cells of the body. Chromosomes have structures on their ends called telomeres. With time, much like the fraying edges of a well-worn map, 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 Parkinson’s. 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 Parkinson’s, 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, WA
Total Award Amount: $165,000 over two years

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 Parkinson’s. 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 Parkinson’s.

Small Aromatic Molecules as Novel Inhibitors of Alpha-Synuclein Aggregation

Daniel Segal, Ph.D.
Tel Aviv University
Total Award Amount: $165,000 over two years

The hallmark of Parkinson’s disease is the accumulation and clumping together of alpha synuclein protein in certain brain cells. Such protein aggregation is typical of other neurodegenerative diseases as well. In Alzheimer’s disease, for example, beta-amyloid protein accumulates in brain cells. In previous studies, Dr. Segal synthesized a small molecule that, because of its shape, prevents beta-amyloid molecules from sticking together. When administered in laboratory tests on fruit flies and mice, it inhibited beta-amyloid clumping, reversed cognitive problems in the laboratory animals, and reduced amyloid deposits in their brains. Bringing these ideas to Parkinson’s, Dr. Segal also has shown that his synthetic molecule inhibits the aggregation of alpha synuclein in the Petri dish. His goal is to extend this research to studies with fruit flies and mice, and to use his results thus far to refine the structure of the molecule. Ultimately, this research may lead to a therapy that could alter the progression of Parkinson’s.

Identification of Genes for Parkinson’s Disease in an Isolated Greek Community and a Greek Population Cohort

Georgia A. Xiromerisiou, M.D., Ph.D., with Henry Houlden, M.D., Ph.D.,M.R.C.P.
University of Thessaly and University College London
Greece and England
Total Award Amount: $165,000 over two years

Scientists have recently identified several genes that, when mutated, cause rare inherited forms of Parkinson’s disease. In an effort to identify new Parkinson’s mutations, Dr. Xiromerisiou will study the DNA of people who live in and around the isolated village of Rapsani in central Greece, where the prevalence of Parkinson’s is high. Study participants with Parkinson’s do not have any of the genetic variants that are known to contribute to Parkinson’s. Using standard techniques for genome sequencing, Dr. Xiromerisiou will analyze the DNA of 30 people from the village who have Parkinson’s, unaffected members of families with many cases of Parkinson’s, and healthy individuals. In addition, DNA will be analyzed from people in the surrounding region of Thessaly, including 385 people with unexplained Parkinson’s and 335 healthy people of similar age, gender and ethnicity. The goal is to discover regions of DNA shared by people with Parkinson’s but not by healthy people. The long-term understanding of Parkinson’s continues to be shaped by genetic studies; therefore, a genetic answer as to why this group is susceptible to Parkinson’s is likely to further focus how scientists approach Parkinson’s research.

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Research Fellowship Grants


Development of a Progressive Neurodegenerative Mouse Model of Parkinson's Disease

Ane Korff, Ph.D.
St Jude Children's Research Hospital
Memphis, TN
Total Award Amount: $47,500 over one year

A critical tool in a scientist’s quest to understanding the cause(s) of and developing a possible treatment for Parkinson’s disease is the animal model, an animal that has been bred to mimic aspects of Parkinson’s.  Progress in Parkinson’s has been hampered to date because scientists have not had a model that accurately mimics the progression of Parkinson’s in humans.  For instance, the slow and progressive loss of dopamine neurons and the inflammatory processes found in the aging human brain do not exist in the mouse brain.

This study aims to create and test a new mouse model by crossbreeding transgenic mice with different genetic characteristics. The idea is that this new mouse model would more accurately replicate the affects of Parkinson’s upon brain structures such as the basal ganglia and locus coeruleus.  Dr. Korff will test the new mouse model by designing experiments that compare and contrast existing mouse models to the new model.  If successful, a new and improved mouse model could help scientists identify the mechanisms underlying neurodegeneration and facilitate the development of drugs that might alter the progression of Parkinson’s.

Evaluating Pedunculopontine Nucleus Stimulation as a Treatment for L-DOPA-resistant Gait Disorders in Advanced Parkinson’s Disease

Abirami Muralidharan, Ph.D.
University of Minnesota
Minneapolis, MN
Total Award Amount: $47,500 over one year

People with Parkinson’s have increasing difficulty walking as the disease progresses. Therapies such as medications that raise brain levels of dopamine, and deep brain stimulation (DBS) surgery, can help tremor, slowness and stiffness, all of which affect walking. But they are not effective in overcoming difficulties such as initiating a step (akinesia) or with balance. At this time, DBS therapy targets one of two regions in the brain, the subthalamic nucleus or the globus pallidus. This study will investigate the effects on gait and balance of DBS in a third brain area — the pedunculopontine nucleus (PPN). First Dr. Muralidharan will characterize the electrical properties of PPN neurons in normal nonhuman primates and compare the results with those measured in nonhuman primates that have Parkinsonian symptoms. Then he will assess the effect of DBS of the PPN on gait and balance in the Parkinsonian primates, in part by measuring their ability to use a specially designed treadmill. Finally, he will study the primate brains postmortem to confirm that electrical stimulation was delivered accurately within the brain by the DBS apparatus. These studies may help us understand if DBS surgery could be used differently to better help with akinesia and balance problems.

The Role of Parkin in Regulating Mitochondrial Dynamics and Homeostasis in Cortical and Dopaminergic Neurons

Victor Van Laar, Ph.D.
University of Pittsburgh
Pittsburgh, PA
Total Award Amount: $47,500 over one year

Inside all cells of the body are structures called mitochondria, which produce energy. Damage to mitochondria in certain cells in the brain has been linked to Parkinson’s disease and other neurodegenerative diseases. Scientists also have shown that the gene known as Parkin plays a role in keeping mitochondria healthy. Mutations in Parkin are one of several, rare inherited causes of Parkinson’s. This study investigates how mutated Parkin affects mitochondria in two different types of brain cells: dopamine neurons (the neurons whose death leads to Parkinson’s motor symptoms) and neurons in the brain’s cortex, which tend to be affected later in Parkinson’s. In experiments with rat neurons grown in laboratory dishes, Dr. Van Laar will use molecular techniques to manipulate Parkin levels in the cells and assess the effects on mitochondria. A clearer understanding of how changes in mitochondria lead to neurodegeneration and cell death may suggest new approaches to therapies that slow the progression of Parkinson’s.

The Locus Coeruleus as a Substrate for Parkinsonian Cognitive Inflexibility

Elena Vazey, Ph.D.
Medical University of South Carolina
Charleston, SC
Total Award Amount: $47,500 over one year

In addition to movement symptoms such as tremor and rigidity, many people with Parkinson’s disease experience cognitive changes. These can include slowed thinking and trouble shifting between tasks, or multi-tasking. Medications that raise the level of the chemical dopamine in the brain help movement, but are not effective against cognitive symptoms. This study focuses on a part of the brain stem called the locus coeruleus, which produces a different chemical messenger — norepinephrine. Research suggests that degeneration of the locus coeruleus in Parkinson’s contributes to cognitive symptoms as well as changes in sleep and mood. In studies with rats, Dr. Vazey will investigate the cognitive effects of raising and lowering levels of norepinephrine in the locus coeruleus. This will lead to an improved understanding of the role of the locus coeruleus in cognitive function, and assess the potential of regulating norepinephrine as a therapy for cognitive symptoms in Parkinson’s.

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