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Featured Research

What can we learn by studying genetics and Parkinson's? PDF-funded researchers Drs. Mata and Zabetian share their progress six years after launching the first large-scale survey of PD genetics in Latin America.

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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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2014 Investigator-Initiated Projects

Among PDF's research awards of $5.1 million in 2014, we are funding 15 novel investigator-initiated research projects via two core programs that encourage early-career scientists to test out their most daring ideas – International Research Grants and Research Fellowships.

Abstracts of these projects appear below.

International Research Grants

[+] Epigenetic Dysregulation in Levodopa-Induced Dyskinesia*

David Anderson, Ph.D., and  Jay Schneider, Ph.D., Thomas Jefferson University, Philadelphia, PA

After long-term treatment with levodopa, some people with Parkinson’s disease experience a side effect called levodopa-induced dyskinesia (LID). Scientists are uncertain what causes these involuntary twisting and writhing movements, but certain brain cells could be responsible. Perhaps levodopa triggers a key event that controls multiple types of brain cells, which together cause LID. We wondered if a cellular event called DNA methylation could be this key event. The body uses DNA methylation to turn genes on or off. Researchers have already shown that taking levodopa can change DNA methylation levels in people with PD. We will study animals with PD-like symptoms. About half of the animals take levodopa and experience LID. We will compare DNA methylation in animals with and without LID, looking for genes in the brain that are methylated differently between the two groups. In this way, we may identify genes linked to LID, which could provide new clues to how this side effect develops and suggest new strategies to prevent or treat it.

[+] Elucidation of the Role of Cholinergic Interneurons in Levodopa-Induced Dyskinesias Using Transgenic Rats and AAV-mediated Overexpression of Modulatable Receptors*

Tomas Björklund, Ph.D., Lund University, Lund, Sweden

After long-term treatment with levodopa, some people with Parkinson’s disease experience a side effect called levodopa-induced dyskinesia (LID). Scientists are uncertain what causes these involuntary twisting and writhing movements. But there is suspicion that brain cells called cholinergic interneurons are involved. Our research aims to better understand how these cells contribute to LID. We will work with rats with PD-like symptoms that are receiving levodopa treatment. We will observe what happens when we first activate and then quiet cholinergic interneurons. In this way, we can find out whether signaling these cells really worsens LID, as we hypothesize. In another set of experiments, we will compare the actual cholinergic interneurons from the brains of rats with and without LID, looking at which genes are turned on and off in the cells. These experiments may provide clues as to which genes scientists should target to treat LID in people. Thus, this project is expected to provide new insights into the role of cholinergic interneurons in LID and suggest new targets for therapy to control this debilitating side effect.

[+] Interaction of LRRK2 and Tau in Mediating Neurodegeneration in Mouse Models of Parkinson's Disease*

Darren J. Moore, Ph.D., Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland

Cases of inherited Parkinson’s disease are rare. But when they occur, mutations in the LRRK2 gene are one of the most common causes. Autopsies have shown that the brains of people with LRRK2 mutations contain abnormal clumps of various proteins, including alpha-synuclein and tau. In addition, recent studies have revealed that tau accumulates in the brains of rodents with LRRK2 mutations. Most prior research has focused on the contribution of alpha-synuclein clumps, or Lewy bodies to PD. But we wondered whether tau might cooperate with mutated LRRK2 to harm dopamine neurons in Parkinson’s disease. To answer this question, we will study mutated LRRK2 in cell cultures and in rats, observing whether tau is required for the neuron death. Also, we will examine whether normal LRRK2 is required for the neurodegeneration observed in mice that produce mutated tau. These studies may uncover interactions between LRRK2 and tau that contribute to neurodegeneration in PD. Understanding these interactions could help develop new drugs that interfere with the actions of either or both proteins to prevent or treat PD.

[+] Identifying Connectivity Changes with Deep Brain Stimulation in Parkinson’s Disease*

Matthias L. Schroeter, M.D., M.A., Ph.D., and Karsten Mueller, Ph.D., Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Sachsen, Germany

In recent years, deep brain stimulation (DBS) has been established as a successful surgical method for treating some people with Parkinson’s disease. DBS provides a small electric current to structures of the brain in order to block motor symptoms of PD. The technique involves the surgical insertion of tiny electrodes deep into the basal ganglia region of the brain and the implantation of an impulse generator (similar to a pacemaker) under the person’s collarbone to provide an electrical impulse to their brain. However, it is still unknown how DBS improves motor symptoms. One idea is that the treatment may alter connections among circuits of neurons, or neural networks, in the brain. We plan to investigate how neural networks change with DBS and compare these changes with those caused by Parkinson’s medications. We will use a brain scan called functional magnetic resonance imaging (fMRI) to study resting state brain activity before and after taking PD medications, and with and without DBS. By examining a person’s brain images before treatment, we may be able to predict their response to the treatment. In this way, we could identify people who would benefit from DBS before they undergo surgery. We expect this research project to advance our knowledge of PD and our understanding of therapeutic approaches.

[+] Novel Insights into the Properties and Fate of Naturally Secreted Alpha-synuclein

Georgia Sotiropoulou, Ph.D., University of Patras, Greece

Scientists know that a protein called alpha-synuclein plays an important role in the death of certain brain cells, and that this cell death leads to Parkinson’s disease. It is also well known that alpha-synuclein forms toxic clumps inside of certain brain cells. But alpha-synuclein is also found outside of cells. One theory holds that the risk of PD increases when there is too much alpha-synuclein circulating outside of cells. This research project focuses on an enzyme, kallikrein-related peptidase 6 (KLK6), which may help break down and clear excess alpha-synuclein. We seek to understand, step-by-step, how levels of alpha-synuclein outside of cells are regulated. We are also looking for links between these levels and the development of PD. If the enzyme KLK6 is found to play a role in regulating alpha-synuclein levels, it provides a clue for developing new drugs. For example, it would demonstrate that drugs that increase the activity of KLK6 might have potential as PD therapies.

[+] Striatal CaV1.3 Calcium Channel Silencing as a Neuroprotective Target for Levodopa-induced Dyskinesias

Kathy Steece-Collier, Ph.D., and Frederic P. Manfredsson, Ph.D., Michigan State University, East Lansing, MI

Levodopa is the gold-standard therapy for Parkinson’s disease. But after taking levodopa for several years most people develop dyskinesias – involuntary movements that are a side effect of the medication. Research has shown that when cellular calcium channels (the gateways that allow calcium into cells) are disrupted, the disruption plays a role in dyskinesias. In particular, one channel called CaV1.3 is implicated. Drugs already on the market for high blood pressure, called calcium channel blockers, are being investigated to treat dyskinesias. But they are not specific to CaV1.3, and thus only partially effective. This research, carried out in rats, investigates whether selectively blocking CaV1.3 might better protect against dyskinesias, and whether it can reverse dyskinesias after they have developed. The results will inform the development of calcium blocking therapies targeted at levodopa-induced dyskinesias.

[+] Imaging Impulsive Control Disorders in PD*

Antonio Strafella, M.D., Ph.D., FRCPC, Toronto Western Hospital, Toronto, Ontario, Canada

Some people who take dopamine agonists to treat motor symptoms of Parkinson’s disease (PD) develop side effects such as compulsive eating, gambling, shopping, or sexual activity. Together, these side effects are called impulse control disorders (ICDs). Scientists suspect that dopamine agonists may change the way some people’s brains perceive risks and rewards. As a result, some people who take dopamine agonists may have trouble controlling harmful behaviors that produce temporary feelings of pleasure or “highs.” We plan to use a type of brain scan – positron emission tomography (PET) scanning – to examine the brains of people with PD, with and without ICDs. Each participant will be injected with a small amount of a radioactive “tracer” that will allow us to observe dopamine levels in the brain. By comparing the scans of people with PD who suffer from ICDs to scans of people with PD who do not have an ICD, we may be able to determine brain differences that cause some people to develop ICDs. Understanding these differences may help better diagnose and treat ICDs in people with PD.

[+] Neuroprotection by XPro1595 in a Chronic MPTP Monkey Model of Parkinson’s

Malú Tansey, Ph.D., and Yoland Smith, Ph.D., Emory University, Atlanta, GA

Brain scans show that people with PD have more inflammation (the body’s response to injury or infection) in their brains than is normal. And studies suggest that drugs to treat inflammation may lower PD risk. We have already shown, in research on rodents with PD-like symptoms, that a new anti-inflammatory drug called XPro1595 penetrates into the brain and lessens and slows brain cell degeneration. Our new study will test the drug in monkeys that have been given MPTP, a substance that kills dopamine neurons and results in PD movement symptoms. If it is effective, XPro1595 will block or reduce the effects of the MPTP. This is an important step in moving this drug toward clinical trials in humans.

[+] Dysfunctional Signalling Mechanism of Neurotransmission in Parkinson’s Disease

Zhenyu Yue, Ph.D., Icahn School of Medicine at Mount Sinai, New York, NY

The neurons affected by PD use a chemical messenger called dopamine to help tell the body to move. Understanding how dopamine communicates is vital to developing new therapies for Parkinson’s disease. We recently identified a mutation in a gene that causes early-onset PD, which may help us to understand dopamine communication. This gene in which we found the mutation is responsible for a protein known as synaptojanin 1 (synj1), which plays a role in the transmission of dopamine from cell to cell. Our study uses novel laboratory methods to investigate the normal role of synj1 and what goes awry when it is mutated. In addition, we will study how synj1 interacts with another PD-causing gene, called LRRK2. A mutation in LRRK2 results in decreased dopamine transmission, which we think may because synj1 is impaired. Knowledge of how synaptojanin 1 mutations may cause PD could provide new targets for therapeutic intervention in PD.

Research Fellowship Grants

[+] Functional Study of the Newly Identified Autosomal Recessive Early-onset Parkinsonism-associated Mutation in Sac1 Domain of Synaptojanin 1

Mian Cao, Ph.D., mentor: Pietro De Camilli, M.D., Yale University, New Haven, CT

Researchers have recently identified a gene called synaptojanin 1, which, when mutated, causes early-onset Parkinson’s disease. To gain insight into the underlying cause of PD, we will investigate the molecular details of how the mutation causes disease. The mutation affects the dopamine neurons, the ones affected in Parkinson’s disease. The cells store dopamine in compartments known as synaptic vesicles. We hypothesize that the synaptojanin 1 mutation disrupts the normal activity of the vesicles, including their ability to release dopamine and re-form their spherical shape afterward. We will use biochemical and imaging techniques, as well as mice engineered to have synaptojanin 1 mutations, to carry out these studies. Knowledge of how synaptojanin 1 mutations affect dopamine release could provide new targets for therapeutic intervention in PD.

[+] Optogenetic Dissection of the Role of Dopamine in Fine Motor Control

Damien J. Ellens M.D., mentor: Daniel K. Leventhal, M.D., Ph.D., University of Michigan, Ann Arbor, MI

Scientists have long known that the chemical messenger dopamine plays an important role in Parkinson’s disease and replacing it with drugs can ease the movement symptoms of PD. But scientists still do not understand exactly why the drugs work like they do. In addition to being in charge of the body’s normal movements such as walking, dopamine also is needed for learning new motor skills. This research takes advantage of a technique called optogenetics to study dopamine neurons in the brains of rats as they learn a new reaching motion. With this technique, the dopamine cells can be turned off at specific moments, with millisecond precision, as the rats learn and carry out their new skill. The goal is to separate and understand the different and distinct functions of dopamine in learning and performing movements. By understanding how distinct dopamine functions contribute to the motor symptoms of PD, scientists can design new drugs, which more effectively ease symptoms and minimize side effects seen with current drugs.

[+] Functional Analysis of Dopamine-dependent Circuits Activity in Parkinson's Disease

Nan Li, Ph.D., mentor: Alan Jasanoff, Ph.D., Massachusetts Institute of Technology, Cambridge, MA

A tiny part of the brain called the substantia nigra is densely packed with cells that produce the chemical messenger dopamine. When these neurons die in Parkinson’s disease, the dopamine is lost. Thus, much research has focused on how dopamine released from these dying cells relates to Parkinson’s disease in that part of the brain. However, other brain cells make and release dopamine throughout other parts of the brain. This study uses cutting-edge imaging techniques to visualize the effects of dopamine release, in three dimensions and in near real-time, both in the region of the substantia nigra and across the whole brain. The research will be carried out in normal healthy rodents and rodents engineered to have PD-like movement difficulties. Seeing these broad dopamine activity patterns will lead to a better understanding of what happens in the brain with different PD symptoms, and further our understanding of dopamine’s role in PD.

[+] Cell-specific Functions of the Globus Pallidus in the Basal Ganglia: Distinct Implications in Normal Behavior and in Parkinson's Disease

Amelie Soumier, Ph.D., mentor: Aryn H. Gittis, Ph.D., Carnegie Mellon University, Pittsburgh, PA

Researchers know that a brain region called the globus pallidus plays a role in Parkinson’s movement symptoms. In fact, deep brain stimulation, a surgical treatment for Parkinson’s disease, sometimes targets this area but it doesn’t help all people. Furthermore, the globus pallidus contains many types of cells, and their relationships to PD movement symptoms are unclear. This study uses a technique called optogenetics to activate specific groups of globus pallidus neurons in laboratory mice as they perform different tasks. Comparing the results from normal mice and mice with low brain levels of dopamine will provide insight into how different cell types in the globus pallidus affect movement normally, and in PD.

[+] In Vivo Modulation of Alpha-synuclein Phosphorylation: Tracking Aggregates in the Living Mouse Brain

Kateri J. Spinelli, Ph.D., mentor: Vivek K. Unni, M.D., Ph.D. Oregon Health & Science University, Portland, OR

In Parkinson’s disease, brain cells that help control the body’s movement accumulate toxic clumps of a protein called alpha-synuclein. Alpha-synuclein can undergo a chemical reaction called phosphorylation, and phosphorylation is associated with the proteins sticking together. Still, scientists are uncertain whether phosphorylation itself is a toxic or a protective reaction. In this study we will watch how alpha-synuclein forms clumps in the brains of living mice. We will make alpha-synuclein visible with a fluorescent tag, treat the mice with a drug that inhibits phosphorylation, and use an imaging technique to watch whether and how alpha-synuclein sticks together. Understanding whether phosphorylation is helpful or harmful might lead to new PD therapies – therapies that could either increase or decrease the change to alpha-synuclein, potentially altering the course of the disease.

[+] A Novel Function of the PINK1/Parkin Pathway in Regulating Oxidative Phosphorylation through mRNA Localization and Translational Control

Zhihao Wu, Ph.D., mentor: Bingwei Lu, Ph.D., Stanford University School of Medicine, Stanford, CA

Scientists have identified several genes that are responsible for inherited forms of Parkinson’s disease. Two of these genes are called PINK1 and Parkin. Within individual cells, PINK1 and Parkin are active in structures known as mitochondria – the cell’s energy factory. This research investigates the molecular processes by which energy is produced in the mitochondria and the roles of PINK1 and Parkin in these processes. In earlier research, we discovered new functions for PINK1 and Parkin in building the internal mitochondrial machinery. Our goal is a more thorough understanding of how these two PD genes are used by cells to build new mitochondria and break down old ones, and how disrupting these activities underlies the development of PD. This study has the potential to open new directions in PD research and offer new therapeutic targets for intervening in PD.

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*Denotes second year of funding