Browse summaries of 2017 Parkinson's Foundation-supported research grants. Throughout the year, stay tuned for more announcements of the ways we work to better understand Parkinson's disease (PD).
Stanley Fahn Junior Faculty Awards: $1.8 Million (Three-Year Award)
Direct Imaging of the Cause and Treatment of Parkinson's Disease with Synthetic Modulatory Neurotransmitter Nanosensors (2017)
Markita Landry, Ph.D., University of California, Berkeley
Parkinson's develops when levels of the chemical messenger dopamine decline in the brain. Standard PD therapies work by raising dopamine levels. However, there is no way to measure changes in these levels quantitatively — for example, to understand how well a drug works. That's because dopamine is difficult to detect in the brain and because the area affected by PD is deep within the brain and difficult to scan. In studies with mice, we are developing new infrared dopamine nanosensors that can detect the brain's use of dopamine in real time — in the short term, such as after a physical therapy session or after a dose of medication, as well as throughout long-term disease progression. Our goal with this imaging technique is to provide a quantitative basis for evaluating drug effectiveness and dosing, rather than relying on trial and error and observation of symptoms.
Deconstructing the Behavioral Neuropharmacology of Parkinson's Disease (2017)
Michael R. Tadross, M.D., Ph.D., Duke University
Many scientists are trying to develop drugs to circumvent the side effects of standard PD medications. But the fact that the brain area affected — the striatum — consists of several types of cells, all tightly intermingled stymie their efforts. The non-dopamine therapies have helped some cell types while harming others, canceling out any benefit. We are using a new method called DART (Drugs Acutely Restricted by Tethering), to ensure sending a drug only to one isolated cell type. With this technique, we are mapping which cell types receive a benefit and which are responsible for side effects for several classes of drugs. The results will ultimately reveal insights into the causes of Parkinson's and will guide development of new targeted therapies.
In Vivo Systems-Based and Unbiased Approaches to Study Alpha-Synuclein Toxicity (2017)
Maxime Rousseaux, Ph.D., Baylor College of Medicine
In Parkinson's, abnormal forms of a protein called alpha-synuclein form clumps within the brain's dopamine neurons. A hallmark of PD, these clumps (called Lewy bodies) associate with cell death. But scientists know little about what happens after a cell produces alpha-synuclein — what substances does it interact with and why does it clump together? Using new genetic and protein-screening technologies, we will identify proteins that bind to alpha-synuclein and increase or decrease alpha-synuclein levels. This, in turn, will shed light on how alpha-synuclein becomes toxic. We will focus on known proteins that become altered in PD, and that conventional drugs can target. This will lead us to a handful of promising candidates for new PD therapies, which can be laboratory tested.
High Throughput in Vivo Screens for Targeted Parkinson's Disease Gene Therapies (2016)
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.
Parkinson's Genetic Risk Factors in Latino Populations (2016)
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.
Direct Pathway Striatal Activity in Dyskinesia (2016)
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.
Postdoctoral Fellowship Awardees: $1.5 Million (Two-Year Award)
White Matter Templates in Parkinson's Disease (2017)
Derek Bradley Archer, Ph.D., Mentor: David Vaillancourt Ph.D., University of Florida
Scientists studying Parkinson's are intensely searching for a biomarker — a blood test, brain scan or other objective measurement — that can definitively diagnose Parkinson's and act as a disease progression measure. Some of this research focuses on analyzing specific brain regions in people with PD. But the nerve fibers that connect brain regions, known as white matter or tracts, are also important.
We will use a scanning technique called diffusion MRI to create a map of the brain tracts affected by Parkinson's. Then we will use this map to assess Parkinson's and its progression in 151 people with PD and compare the results with scans from 87 people without Parkinson's. We aim to develop a way to quantify brain changes associated with Parkinson's, to improve diagnosis and treatment.
D620N VPS35 Knockin Mice: A New Model of Familial Parkinson's Disease (2017)
Xi Chen, Ph.D., Mentor: Darren Moore, Ph.D., Van Andel Institute
In a small percentage of cases, genetic mutations directly cause Parkinson's. One gene that can cause PD is known as VPS35. Little is known about how the VPS35 protein interacts with other proteins in nerve cells. We will genetically engineer laboratory mice to have a mutated VPS35 gene that is similar to the mutated form found in humans. We will study motor symptoms, dopamine levels, loss of dopamine neurons and other brain cell changes in these mice. We also will investigate how VPS35 interacts with two other proteins involved in Parkinson's — tau and alpha-synuclein. Understanding these interactions could help us to develop new drugs that interfere with the actions of either or both proteins to prevent or treat PD.
Mitochondrial Protein Homeostasis in Peripheral Axons (2017)
Jill Falk, Ph.D., Mentor: Thomas Schwarz, Ph.D., Harvard Medical School/Children's Hospital Boston
Mitochondria are the powerhouses of cells — tiny structures that produce energy from nutrients. Neurons, including the brain cells affected by Parkinson's, need lots of energy to exchange signals with other neurons. So, these cells are constantly replenishing their mitochondria. A lot of research has focused on the PD-affected cells that have trouble disposing of damaged mitochondria.
Our project investigates the supply end of the process — how do cells replace worn-out mitochondria with healthy new ones? Made in the central cell body, these structures must distribute evenly throughout the long cellular "arms," or axons that stretch out to connect with other neurons, creating a challenge. Finding ways to improve the supply of healthy mitochondria to axons could lead to new PD therapies.
Expanding Human Dopamine Neuronal Progenitors for PD Therapeutic Development (2017)
Xiang Li, Ph.D., Mentor: Su-Chun Zhang, Ph.D., University of Wisconsin-Madison
Parkinson's develops when brain cells that normally produce the chemical messenger dopamine sicken and die. Among the approaches to treating the disease — as opposed to current therapies which treat and mask symptoms — are to develop therapies that rejuvenate sickened cells by slowing or preventing their death or to replace the dying cells with healthy ones. Both approaches require large quantities of dopamine neurons of uniform quality. To meet that need, we will develop a "cocktail" that will allow us to grow billions of dopamine neurons starting with relatively few human pluripotent stem cells — cells that have the potential to develop into different cell types. Then we will test the cells to be sure they function as dopamine neurons. Our goal is to produce a reliable supply of dopamine neurons for laboratories to use developing new therapies, or in clinical studies of cell transplant therapy.
Role of Cerebellum on Basal Ganglia Cortical Network in Parkinson's Disease (2017)
Nicholas Strzalkowski, Ph.D., Mentor: Zelma Kiss, M.D., Ph.D., F.R.C.S.C., University of Calgary, Canada
In Parkinson's, miscommunication between the nerve cells in different parts of the brain leads to movement difficulties. Recent studies suggest that a part of the brain called the cerebellum is involved in tremor. This study will investigate the role of the cerebellum in relation to two other brain areas, the basal ganglia and the motor cortex and how this affects tremor. We will study people who have recently undergone surgery for deep brain stimulation, a PD treatment that implants electrodes (wires) in the basal ganglia. While recording basal ganglia activity, as well as signals from the motor cortex (with electrodes placed on the scalp), we will measure arm movement before and after temporarily shutting down activity in the cerebellum. A better understanding of the role of the cerebellum in PD may contribute to new therapies.
Dynamic Interaction Between Striatal Dopaminergic and Cholinergic System in Regulation of Beta-band Oscillations as Mechanisms Underlying Pathophysiology of Parkinson's Disease (2016)
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.
Investigating the Function of Mitochondrial Derived Vesicles in Neurons and Their Role in Parkinson's Disease (2016)
Rosalind Roberts, 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.
Loss of Glucocerebrosidase Increases Dopaminergic Neuronal Vulnerability by Impairing Autophagic Flux (2016)
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.
Alpha-synuclein Mediated Toxicity in the Aged Rat Brain: Molecular Mechanism of the Nucleus (2016)
Ivette Martinez Sandoval, Ph.D., 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 (2016)
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.
Translational Research Grants: $600,000
These aim to ease PD-related cognition, sleep and fatigue difficulties, topics selected as part of our Community Choice Research Awards.
Impact of a Novel Exercise Intervention on Executive Function and Sleep in People with Parkinson's (2017)
Amy Amara, M.D., Ph.D., University of Alabama at Birmingham
Non-motor symptoms such as cognitive difficulties and sleep problems can be more disabling than motor symptoms for many people with Parkinson's. Currently available medications are either ineffective in treating cognition and sleep or offer unwanted side effects. Other therapeutic options such as exercise are known to improve the motor symptoms of PD, but need further exploration for cognition and sleep effects.
This study will examine how a 16-week exercise program, compared to no exercise, impacts cognition and sleep in Parkinson's. Participants will undergo cognitive and sleep testing to measure changes before and after the program. This research aims to identify a cognition and sleep-improving exercise program for people with Parkinson's.
Remotely Supervised Transcranial Direct Current Stimulation (tDCS) for At-home Treatment of Fatigue and Cognitive Slowing in Parkinson's Disease (2017)
Milton Biagioni, M.D., New York University
There is no current effective treatment available for fatigue and slowed thinking, both common PD symptoms. This study is testing an at-home brain stimulation device, along with cognitive training, to see if the dual therapy can ease both symptoms.
Participants can use the low-cost, relatively safe, non-invasive brain stimulation technique, called transcranial direct current stimulation (tDCS), at home. The computer-based cognitive training exercises work to strengthen cognitive abilities. The study will offer the therapies online, enabling people who have trouble getting to the clinic to take part from home. If the treatment works, the results will guide future brain stimulation research to validate this therapy for fatigue and slowed thinking.
Goal-directed Behavior in Parkinson's Disease (2017)
Nabila Dahodwala, M.D., University of Pennsylvania
Cognitive impairment and apathy are common symptoms that can be disabling for people with Parkinson's and caregivers. Our hypothesis is that these symptoms result from fewer "goal-directed behaviors." Goal-directed behaviors are activities done with purpose (for example, reading a book) versus habits or reactions, such as automatically laughing at a joke.
This study will test a new way of measuring goal-directed behavior in Parkinson's. It will also use brain imaging to observe brain changes that occur when people experience apathy and cognitive impairment. The hope is that the study will shed light on the mechanisms underlying apathy and cognition in PD and help in more easily diagnosing them. This knowledge will ultimately allow for the development of targeted PD treatments.
Multi-modal Neuroimaging of Fatigue in Parkinson's Disease (2017)
Hengyi Rao, Ph.D., University of Pennsylvania
Fatigue is a common PD symptom and a major contributor to stress and disability. However, because we know so little about its biological causes, it is difficult to find ways to prevent and manage it. This study will use neuroimaging to observe the brain changes underlying fatigue in Parkinson's. It will also explore the use of blue light as a potential treatment. A therapy exposing the eyes to blue light has proven to decrease daytime sleepiness in people with traumatic brain injuries. This study will explore whether this remedy may also be beneficial for easing fatigue in people with Parkinson's by increasing blood flow in the brain.
Double-blind, Randomised, Cross-over, Pilot Study of Cannabidiol in People with Parkinson's and RBD Sleep Disorder (2017)
Renata Riha, M.D., University of Edinburgh
Many people with Parkinson's suffer from rapid eye movement sleep behavior disorder (RBD), a condition where people experience violent movements (e.g., punching, kicking), during sleep. We will test cannabidiol (CBD), one of the 100-plus active ingredients in marijuana, to see if it can help people with Parkinson's who experience RBD. We will randomly assign participants to receive either CBD or a placebo for the first three months. After three months, the groups will switch — those who took CBD will take the placebo, and vice versa. At the beginning of the study, and at three and six months, participants will undergo several assessments, including an in-home sleep study to assess limb movements during sleep, blood and urine tests, and questionnaires about sleep, mood, symptoms and impact on care partners. The hope is that the results will show whether CBD can help to improve sleep and quality of life for individuals with Parkinson's and their families. The results of this trial will inform clinical practice and allow for future clinical trials.
Characterization of Gastrointestinal and Neuroenteric Dysfunction in Parkinson's Disease (2017)
Amol Sharma, M.D.; Augusta University
Patients with Parkinson's often suffer from debilitating gastrointestinal (GI) issues in addition to many other motor and non-motor symptoms. These can manifest as delayed stomach emptying, gas/bloating, and severe constipation. However, the specific details of GI complaints by PD patients are poorly understood. We seek funding to better characterize GI issues in PD patients, and define the underlying mechanisms by investigating GI symptoms, studying movement of food through the digestive tract, and characterizing communication between the gut and the brain. This study will foster collaboration between movement disorder neurologists, PD patients and gastroenterologists to provide critical information that can lead to innovative therapies in the future to treat GI dysfunction in PD.