“I hope that this might lead to the development of targeted genetic therapies for PD.”
James Dahlman, Ph.D.
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2016 Investigator-Initiated Projects
PDF is funding several innovative investigator-initiated research projects in 2016. Read summaries of these projects below.
[+] Role of Direct Pathway Striatal Activity in Dyskinesia
Alexandra Nelson M.D., Ph.D., University of California, San Francisco
The gold standard treatment for Parkinson’s movement symptoms is levodopa, often prescribed as Sinemet®. But after taking this medicine for several years, many people develop troublesome involuntary movements called dyskinesias. In studies with laboratory mice engineered to have Parkinson’s symptoms, we will investigate how levodopa changes brain activity to both improve movement and to cause dyskinesias. Using a technique called optogenetics, we will monitor the activity of two types of cells in a critical brain area called the striatum, both before and after levodopa treatment. Then we will compare the responses. We believe that the activity of one type of cells may closely mirror the beneficial responses to levodopa, while the other may closely mirror the disabling, dyskinetic responses. A better understanding of these two groups of cells will help in the development of Parkinson’s therapies that provide the benefits of levodopa while minimizing the side effects.
[+] Parkinson’s Disease Genetic Risk Factors in Latino Populations
Ignacio Fernandez Mata, Ph.D., University of Washington
In recent years, dozens of genetic mutations have been identified that either cause Parkinson’s directly or increase a person’s susceptibility to developing the disease. All of these genes have been discovered in populations of European or Asian ancestry. Little is known about their role in Latinos, who carry a mixture of genes from indigenous Americans, Europeans and Africans. In earlier studies we have identified 2,000 people with PD in six South American countries and matched them with 2,000 healthy controls. Our study will genetically screen blood samples from these individuals to identify new susceptibility genes in Latinos. In families with many members affected, we will also sequence all known genes that cause PD in order to identify new genetic variants that cause PD. These data will be crucial in understanding the role of genetics in Latinos with PD, and will allow Latinos to participate in clinical trials for potential treatments targeted toward individuals with specific genetic variants.
[+] High Throughput In Vivo Screens for Targeted PD Gene Therapies
James Dahlman Ph.D., Georgia Institute of Technology
DNA and RNA therapies are a promising new approach to gene therapy for Parkinson’s. But, as with all therapies taken by mouth, researchers need to overcome the difficulties of getting these drugs through the digestive system and past the blood-brain barrier to the specific brain cells where they are needed. One way to do this is to encase the DNA or RNA therapy inside a protective chemical structure called a nanoparticle. Nanoparticles, like other investigational treatments, must be tested in laboratory animals. To date, the expense of these experiments has greatly limited the number of nanoparticles that could be studied. Using a cutting-edge system that our team has designed, we will be able to test 10,000 nanoparticles in mice to find the ones that are best at delivering DNA and RNA therapies to the brain cells affected by PD. Our results will help us synthesize a second generation of nanoparticles that are even more effective.
[+] Dynamic Interaction Between Striatal Dopaminergic and Cholinergic System in Regulation of Beta-band Oscillations as Mechanisms Underlying Pathophysiology of Parkinson’s Disease
Daigo Homma, Ph.D., Mentor: Ann Graybiel, Ph.D., Massachusetts Institute of Technology
The brain cells affected by Parkinson’s use a chemical messenger called dopamine to help tell the body to move. But dopamine plays additional roles related to learning and other behaviors. Our laboratory recently discovered a new one. In experiments with rats, we found that dopamine release surged in the brain’s striatum when the animals were running toward a reward, and were about to achieve their goal. But what happens in PD, when less dopamine is available? We propose that, in this situation, a different set of neurons that use the chemical messenger acetylcholine exert more influence. These neurons are already known to play a role in causing PD movement symptoms. In studies with rats, our research aims to understand how both dopamine and acetylcholine signals, converging in the brain’s striatum, affect motivated behavior. With a tool called optogenetics, we can separately stimulate (or repress) neurons that use these chemical messengers. Our goal is to provide new insight into the mechanisms that underlie PD, which may lay the foundation for future therapies.
[+] Loss of Glucocerebrosidase Increases Dopaminergic Neuronal Vulnerability by Impairing Autophagic Flux
Emily Rocha, Ph.D., Mentor: J. Timothy Greenamyre, M.D., Ph.D., University of Pittsburgh Medical Center
Mutations in the gene glucocerebrosidase (GBA), which result in low levels of the GBA enzyme, are the most common genetic mutations linked to Parkinson’s. Normally, in a process called authophagy, GBA enzyme helps cells to clear and recycle waste products, including clumps of the alpha-synuclein protein. But when levels of GBA are are slow, alpha-synuclein clumps form in dopamine neurons. In fact, the clumps are known as the hallmark of PD. This study will be the first to directly measure the effects of lowered GBA enzyme on autophagy in the dopamine neurons of a living animal, the zebrafish. The research will provide insight into the mechanism that causes alpha-synuclein to form clumps when GBA enzyme is reduced or absent. Then, in experiments with rats engineered to have PD-like symptoms, we will use gene therapy to raise GBA enzyme levels, and determine if this enhances autophagy and prevents alpha-synuclein build-up. Ultimately, we aim to provide new insight into the cellular changes that underlie PD and identify potential strategies for therapies.
[+] Investigating the Function of Mitochondrial-Derived Vesicles in Neurons and Their Role in Parkinson’s Disease
Rosalind Roberts B.Sc., D.Phil., Mentor: Edward Fon, M.D., McGill University
Within the body’s cells, structures called mitochondria are known as the powerhouses. They generate energy for the cell. The genes known as PINK1 and Parkin normally play a role in keeping mitochondria healthy. Mutations in these genes cause rare, inherited cases of Parkinson’s, and much research points to mitochondrial damage as a cause of PD. Recent studies show that one way normal (non-mutated) PINK1 and Parkin help mitochondria is by enclosing “garbage” in bubble-like containers called vesicles. The vesicles are then dispatched to a lysosome, the cell’s waste processor. I will use a technique called mass spectroscopy, which separates substances based on their mass, to find out what’s inside the vesicles and what they are made of. I will also compare the vesicles in cells with and without genetic mutations linked to PD, to discover what might go awry to lead to PD. This is the first study of this kind to be carried out in dopamine neurons, the type of cell affected in PD.
[+] Alpha-Synuclein Mediated Toxicity in the Aged Rat Brain: Molecular Mechanisms in the Nucleus
Ivette Sandoval, Ph.D., Michigan State University, Mentor: Timothy Collier, Ph.D., Michigan State University
Scientists have long known that the brain cells that die in Parkinson’s contain a toxic build-up of a protein called alpha-synuclein. They also know that PD is a disease of aging — most people who develop PD do so after the age of 60. This research investigates the mechanisms by which alpha-synuclein harms brain cells. We seek to understand whether changes in brain cells due to aging make them more vulnerable to alpha-synuclein damage. Recent studies suggest that alpha-synuclein affects the way that brain cells “read” their genes — the way they orchestrate which genes are active or dormant at any given time. In experiments with both young and aged rats engineered to have PD symptoms, I will increase alpha-synuclein levels in the specific brain cells affected by PD. Then I will study the effects of excess alpha-synuclein on the molecular mechanisms that turn genes on and off. A better understanding of these mechanisms, and the ability to compare them in young and aging brain cells, may to lead to new targets for PD therapies.
[+] Thalamostriatal Adaptations in Parkinson’s Disease
Asami Tanimura, Ph.D., Mentor: D. James Surmeier, Ph.D., Northwestern University
Much research in Parkinson’s has focused on the loss of brain cells that help to control the body’s movement. These brain cells send signals from a region called the substantia nigra to another called the striatum. But a second less-studied brain region, the thalamus, also sends signals to the striatum. We know that changes to cells in the thalamus, including a build-up of alpha-synuclein protein, happen early in the course of PD. This research will compare signaling from the thalamus to the striatum in two groups of mice — normal mice and mice engineered to have PD-like symptoms — to understand how PD affects these circuits. Already, we have identified changes in two specific signaling pathways. With the recent development of a new PD mouse model, we can manipulate these circuits individually. A better understanding of these circuits in an animal model of PD will allow us to investigate ways to return their activity to normal and potentially alleviate movement difficulties. Ultimately this research could lead to new strategies for PD therapies.
[+] Identifying Elements of the Transcriptional Regulatory Network of PARIS (ZNF746) Involved in α-Synuclein-Induced Neurodegeneration
Preston Ge, Mentor: Ted Dawson, M.D., Ph.D., Johns Hopkins University
The hallmark of Parkinson’s are abnormal clumps, in certain brain cells, of a protein called alpha-synuclein and visible only on autopsy. Although alpha-synuclein build-up is associated with the death of dopamine neurons, scientists do not fully understand their role in PD. We have identified a molecular pathway that may explain the sequence of events. We found that alpha-synuclein clumps lead to the inactivation of a gene called Parkin, which in turn leads to a build-up of another protein called PARIS. PARIS may be the culprit. In fact, mice engineered to lack this protein had less clumping of alpha-synuclein. But we do not know much about PARIS accumulation. My study makes use of genetically-engineered mice to investigate the build-up of PARIS, and how it relates to alpha-synuclein and neurodegeneration in PD. Understanding the role of PARIS in PD could potentially lead to new therapies.
[+] The Interaction of Parkinson’s Disease Gene FBXO7 with Bag2
Dima Hage, Mentor: David Park, Ph.D., University of Ottawa
In most cases, the cause of Parkinson’s is unknown. But in rare instances, an inherited genetic mutation causes PD. For example, people who inherit two copies of a mutated FBXO7 gene — one from their mother and one from their father — develop PD at an early age, often younger than 30 years old. My research investigates how and why FBXO7 mutations cause PD. Earlier studies suggest that the protein produced by FBXO7 (in its healthy non-mutated form) associates with substances in the cell to help remove “garbage” — malformed or damaged proteins. This study uses neurons in cell culture to study whether FBXO7 might interact with a protein called Bag2, to help protect against cellular changes that lead to PD. Ultimately, understanding how the gene works typically, and the molecular pathways that might go awry to cause PD, can help identify targets for potential new therapies.
[+] DBH-ASYN Mouse Model, Effect of Inflammation in Gastrointestinal System
Kiana Khosravian, Mentor: Malú Tansey, Ph.D., Emory University
Parkinson’s symptoms like tremor and stiffness appear after certain cells called dopamine neurons die in the brain. This cell death is attributed to the toxic build-up of a protein called alpha-synuclein. But even before these movement difficulties, people with PD can experience constipation. And one theory holds that the first signs of PD appear in the nerve cells of the digestive tract — alpha-synuclein clumps may originate there and then spread to the brain. Past mouse models of PD have mimicked only cell death in the brain. I will study a new mouse model genetically engineered to produce excess alpha-synuclein in cells throughout its nervous system, including the digestive tract. I will look for alpha-synuclein clumps in the gut of animals between two to 10 months old, and analyze gut tissue for signs of inflammation, which may provide a pathway for alpha-synuclein to spread to the central nervous system and the brain. I will also examine the stomach nerves for signs of neurodegeneration. This research contributes to understanding the underlying causes and development of PD.
[+] The Role of the ESCRT Complex in a Vesicular Trafficking Pathway from Mitochondria to Lysosomes
Sydney Lee, Mentor: Edward Fon, M.D., McGill University
Within cells, structures called mitochondria are the powerhouse. They transform nutrients into chemical energy. Much research links Parkinson’s to damaged mitochondria. One way that cells keep their mitochondria running smoothly is by enclosing damaged pieces in a container called a vesicle. This is a sort of bubble that buds off the mitochondria and carries “garbage” to a disposal site, called the lysosome. My research investigates the role of the Endosomal Sorting Complex Required for Transport (ESCRT), a group of connected proteins, in the formation of these vesicles. Earlier research shows that the ESCRT may play a role in remodeling the vesicles. Two other proteins, called Parkin and PINK1, are also involved. Mutations in these two proteins can cause PD, possibly by gumming up the works of vesicle formation. Understanding the fundamental cellular mechanisms that maintain mitochondrial health can help in identifying targets for potential new PD therapies.
[+] REM Sleep Without Atonia Signatures Help Distinguish Between Synucleinopathy Disorders
Stuart McCarter, Mentor: Erik St. Louis, M.D., Mayo Clinic
During the portion of sleep when a person dreams, their muscles normally become paralyzed. But people with a sleep disorder called REM sleep behavior disorder not only move while dreaming, they also often act out violent dreams or kick during sleep. Studies have suggested that people with REM sleep behavior disorder are at an increased risk of developing Parkinson’s and two other related Parkinson’s plus syndromes — dementia with Lewy Bodies (DLB) and multiple system atrophy (MSA). This research will enroll 75 study participants to test whether different muscle groups are affected by this sleep disorder in people with the different diseases — in effect, whether the different disorders have distinct REM sleep “signatures.” The study also will provide further insight into whether this sleep disorder is associated with an increased risk of PD.
[+] In Vivo Optical Measurement of Direct and Indirect Path Projection Neuron Activity in a Parkinson’s Disease Rodent Model with Treatment of L-DOPA and Cannabinoid Antagonists
Rachel Mikofsky, Mentor: David Sulzer, Ph.D., Columbia University
The movement symptoms of Parkinson’s develop when certain nerve cells called dopamine neuron die in the brain. Dopamine neurons normally produce the chemical messenger dopamine. Their death disrupts nerve cell communication, or firing. My research investigates — at the level of individual cells — how firing rates of surviving neurons change with the loss of dopamine. Using a technique called Time Correlated Single Photon Counting, I will record neuron firing in normal laboratory mice as they traverse a corridor lined with food. Then the mice will be treated with a chemical toxin to destroy dopamine neurons on one side of the brain, simulating PD, and their neuron firing will be recorded as they complete the corridor task again. Finally, I will give the mice two types of levodopa therapies intended to lessen their Parkinsonian symptoms, and record their neuron firing a third time. The results will provide insight into the correlation between the firing of certain neural pathways and movement.
[+] Relevance of Amino Acid Charge/Polarity in New Familial Mutants of Alpha-synuclein
Emily Ong, Mentor: Shubhik DebBurman, Ph.D., Lake Forest College
In rare cases, Parkinson’s disease that runs in families is caused by a mutation in the gene that codes for alpha-synuclein protein. Just one spelling mistake in the instructions for making this protein — the substitution of one letter for another — can cause PD if it happens in certain places. Several such mutations are newly discovered, and it is not known whether the loss of the original letter or the gain of the new one is responsible for PD. Using yeast as a model organism, I will examine these new variants and investigate what happens when four different substitutions are made at the point that caused PD. My goal is to understand whether changes in the chemical properties of the letter substitution — its charge or polarity — drive abnormal processes to understand alpha-synuclein mutations as a whole rather than viewing them as unique, distinct mutations.
[+] Impact of Inflammation on Alpha-Synuclein Expression in the Colonic Enteric Nervous System
Henry Resnikoff, Mentor: Marina Emborg, M.D., Ph.D., University of Wisconsin-Madison
The hallmark of Parkinson’s, identifiable only after autopsy, are clumps of alpha-synuclein protein within certain brain cells called dopamine neurons. These protein clumps also have been found in nerve cells that line the digestive tract of people with PD, including the colon. Constipation is a common early PD symptom and one theory holds that PD begins in the digestive tract. Some researchers have proposed that inflammation in the gut triggers the formation alpha-synuclein clumps. Common marmoset monkeys have a similar set of digestive tract nerves as humans, and also often develop gut inflammation. My study will compare post-mortem tissue from monkeys with and without inflammation of the colon to quantify both alpha-synuclein protein and markers of inflammation. The results will provide insight into the possible cause of alpha-synuclein aggregation in gut neurons, and provide useful data for studying marmoset monkeys as a model for PD in future research.
[+] Association Between Water Source and Incident Parkinson Disease
Maya Silver, Mentor: Brad Racette, M.D., Washington University
Although the causes of Parkinson’s remain unknown, many experts believe that exposure to substances in the environment play a role in triggering the process of brain cell death that leads to PD movement symptoms. Contaminants in drinking water may be among these substances. This study makes use of data from Medicare, the federal health insurance program used by most older adults in the United States. We will determine the numbers of new cases of PD among Medicare beneficiaries in 2009, and use their addresses to determine their source of drinking water. We hypothesize that there is a higher incidence of PD in communities that use private water sources, which do not undergo the same quality monitoring as public water supplies, and in communities whose water supplies may contain industrial contaminants. Identifying potential risk factors for PD in drinking water is critical to forming a strategy to prevent the disease.
[+] Investigation of Dopamine Neuron Degeneration as a Consequence of Microbiome-Derived Bacteria
Samuel Stanley, Mentor: Kim Caldwell, Ph.D., University of Alabama
The human digestive tract contains thousands of types of bacteria, known as the microbiome. Parkinson’s has been linked with changes in the balance of these bacteria, which can occur long before PD symptoms. This study investigates the relationship between substances produced by the human microbiome that trigger inflammation and the onset of nerve cell degeneration and death, the cause of PD. We will culture bacterial species commonly found in the human intestines and feed them to C. elegans, a type of roundworm with a simple nervous system that is often used as a model organism. We can then study bacterial influences on immune pathways in this worm. In particular, we will investigate the effects on dopamine neurons in the worm, the same type of neuron affected by PD in humans. Shedding light on these relationships advances our understanding of the underlying causes of PD.
[+] Parkinson’s Disease Penetrance in Obligate Carriers of SMPD1 Mutations
Adina Wise, Mentor: Roy Alcalay, M.D., M.Sc., Columbia University Medical Center
Niemann-Pick disease is a rare genetic disease that happens when a person inherits two mutated copies of the gene SMPD1, one copy from each of their parents. Recent studies have shown that people who have only one mutated copy of this gene and no Niemann-Pick symptoms are at an increased risk for Parkinson’s. My study aims to quantify this PD risk. At a clinic for people with Niemann-Pick disease, we will use questionnaires to discover whether people with the disease, as well as their parents — who are carriers of one mutated copy of SMPD1 — have been diagnosed with PD or have any of the classical movement symptoms of PD. We will compare the results to the risk of PD among non-carriers of SMPD1 mutations obtained from earlier studies. The results will inform future genetic counseling for people of Ashkenazi Jewish descent, who are at increased risk of Niemann-Pick disease.
[+] High Angular Resolution Diffusion Imaging Correlates of Cognitive Impairment in Parkinson’s Disease
Kali Xu, Mentor: Kathleen Poston, M.D., M.S., Stanford University
Cognitive changes are common, troubling and often debilitating symptoms for people with Parkinson’s. Recent studies have suggested that changes in the structure of the brain’s white matter — the bundles of long nerve-cell fibers that connect different areas of the brain to each other — correlate with specific cognitive symptoms. We are using a brain-scan technique called high angular resolution diffusion imaging (HARDI), which allows us to see these fibers in great detail, to investigate the idea further. The scans have been done, and data collected, on 45 people with PD (22 with cognitive impairment and 22 without) and 14 healthy people matched for age, education, disease duration and severity of movement symptoms. For my project, I will analyze these data to determine whether, and to what degree, white matter changes correlate to cognitive symptoms. Being able to see and monitor such changes is a first step toward treating and preventing them.