Targeting Communication Among Nerve Cells to Improve Motor Symptoms in Parkinson’s

Beatriz Nielsen, PhD of the University of Colorado (a Parkinson’s Foundation Center of Excellence) received a Parkinson’s Foundation Postdoctoral Fellowship grant to study the balance between two neuromodulators — chemical substances that affect communication among nerve cells — and how it is altered in Parkinson’s disease (PD).

The findings may lead to new therapeutic strategies for PD.

A balance between the neuromodulators dopamine (DA) and acetylcholine (Ach), is essential for correctly executing goal-directed movements and habits. Goal-directed movements are conscious and planned motor functions oriented toward a specific goal. Habits are more automatic actions based on past success. An imbalance between the two neuromodulators is related to motor disorders such as Parkinson’s disease.

How ACh plays a role in this nerve cell communication is not well understood. Increased insight is needed to understand Parkinson’s motor dysfunction, and to develop new and more effective therapies. Dr. Nielson will study this question in two animal models of Parkinson’s.

“The first description of Parkinson’s disease was made two centuries ago but finding a cure or more effective therapies with fewer side effects that improve life quality remains a goal that has unfortunately not been reached,” said Dr. Nielsen. “I hope that understanding acetylcholine transmission and how it is altered following dopamine loss in this movement disorder opens doors for the development of new and more effective therapeutic strategies.”

2021 Impact Award   

Targeting Brain Cells That Cause Movement Disorders in Parkinson’s

Rafiq Huda, PhD, of Rutgers University received a Parkinson’s Foundation George G. Kaufman Impact Award to identify a potential therapeutic target for the motor symptoms of Parkinson’s disease (PD). Using cutting-edge technology, he will examine how an understudied group of brain cells called astrocytes contributes to motor dysfunction in PD. Astrocytes are an important component of brain circuits that regulate nerve cell processing.

“Astrocytes are fascinating cells that can do much more in the brain than they currently get credit for,” said Dr. Huda. “My hope is that what we discover in this basic science project will help establish astrocytes as a novel therapeutic target for PD.”

Movement requires coordinated activity across a large brain-wide network. Dr. Huda’s study will test whether astrocytes coordinate this network of activity in the striatum, a part of the brain that integrates motor-related information from many distinct brain regions to regulate movement. Dysfunction of the striatum, which is affected by the hallmark impairment of the production a brain chemical called dopamine in PD, is a key contributor to the disease’s motor symptoms. It is not known how the loss of dopamine affects the function of astrocytes.

Dr. Huda’s lab will focus on clarifying how astrocytes are affected and how their function impacts neuronal elements of the striatum. This research will work to explore how astrocytes contribute to motor symptoms of PD.  

“I wanted to focus my research efforts on topics that are directly relevant for improving the human condition,” said Dr. Huda. “Parkinson’s, and movement disorders generally, impact a significant number of people. Given my background in movement control, I figured I could make the most impact by focusing my lab’s energy on studying how dysfunction of brain processes underlie PD and other movement disorders.”

Of his Impact Award, Dr. Huda said, “The Award has already had a huge impact on the trajectory of my career. Going in new research directions is always very risky, especially with untested ideas. Besides providing financial support, receiving feedback from established and eminent PD researchers on our ideas was instrumental in sharpening our thinking about how to approach this project.”

2021 Impact Award    

Understanding Gender Differences in Parkinson’s

Biological sex has a strong influence on the symptoms and course of Parkinson’s disease (PD). Ellen Hess, PhD, of Emory University, a Parkinson’s Foundation Center of Excellence, received a Parkinson’s Foundation George G. Kaufman Impact Award to study sex differences in PD.

Previous research has established that males are two times more likely than females to develop Parkinson’s. Men also develop the disease at an earlier age than females and are more likely to have bradykinesia (slowness of movement). In later stages, men have increased daytime sleepiness.

“There are very few studies examining the underlying reasons for sex differences in movement disorders but our knowledge of sex differences in the biology of the central nervous system has grown in leaps and bounds in the past few years,” Dr. Hess said.

Women tend to have more Parkinson’s-related tremors. Women also have greater anxiety and depression, and more severe involuntary movements caused by the Parkinson’s medication levodopa. This is called L-DOPA-induced dyskinesias, or LIDs. Some research suggests estrogen may play a role in delaying or preventing Parkinson’s in women, but estrogen is probably not the only explanation for the differences between males and females.

“The biological reasons for the differences between the sexes are largely unknown and unexplored but nonetheless very important because understanding these differences could ultimately lead to personalized and more effective treatments that are targeted to males or females,” said Dr. Hess.

Dr. Hess’s research will examine sex differences in gene expression in basal ganglia in a mouse model of Parkinson’s and LIDs. The findings could lead to the discovery of drugs specifically targeted to male and female patients using a personalized medicine approach.

“Although I have been working in the role of dopamine in movement disorders for my entire scientific career, much of our work has focused on dystonia, this is actually our first grant on Parkinson’s disease,” said Dr. Hess. “The Parkinson’s Foundation grant is providing my laboratory the opportunity to expand the focus of our work and, for the first time, to contribute to Parkinson’s disease research in a meaningful way.”

2021 Impact Award  

Insights Into Brain’s Dopamine System Could Yield New Parkinson’s Treatments

Onur Basak, PhD, of University Medical Center Utrecht - Translational Neuroscience Utrecht, Netherlands, received a Parkinson’s Foundation George G. Kaufman Impact Award to investigate the role of histones (a type of protein found in chromosomes that bind to DNA) in the development and progression of Parkinson’s disease (PD). This research will yield insights into the dopamine system in the brain that may lead to new treatments for Parkinson’s.

Despite decades of research, we still do not know exactly how Parkinson’s disease develops. A major hallmark of the disease is the loss of brain nerve cells called dopaminergic neurons in two regions of the midbrain. These nerve cells produce the brain chemical dopamine. In people with Parkinson’s, the cells that make dopamine are impaired. Current treatment for loss of motor symptoms focuses on dopamine but cannot offer a cure.

“There is a great need for new therapeutic targets for PD. Our research provides a new perspective that has the potential to implicate new molecular processes that can be ‘hijacked’ for therapeutic approaches in the long run,” said Dr. Basak.

Evidence shows that a biochemical process called methylation of histones is altered in people with Parkinson’s. However, how this happens is not well understood. Dr. Basak will study histone methylation in different types of dopamine-related neurons as well as neighboring cells that are indispensable for their function.

As part of his research, Dr. Basak will look at the way epigenetics — the processes that help direct when individual genes are turned on or off — affect the progression of Parkinson’s. In the long run, this study will contribute to efforts to discover new drug targets for Parkinson’s treatment. 

“Investing in fundamental research is the key to finding new venues for treatment, and eventually, a cure for PD,” Dr. Basak said. “Highly ambitious projects can only be carried out with the support of donors supporting this vision, as the Parkinson's Foundation does. This grant will give me the opportunity to turn a highly ambitious aim into reality. Since the grant is prestigious, it will also support my integration in the PD community.”

2021 Stanley Fahn Junior Faculty Award  

Learning How Pesticides Impact Parkinson’s

Tim Sampson, PhD, of Emory University, a Parkinson’s Foundation Center of Excellence, received a Parkinson’s Foundation Stanley Fahn Junior Faculty Award to understand how Parkinson’s-linked pesticides affect the gut microbiome, the complex community of bacteria and other microbes in the intestinal tract.

Studies suggest that people with Parkinson’s disease (PD) harbor distinct gut microbiomes. By identifying gut microbiome changes, the effects of those specific changes on the body, and interactions between environmental exposure and genetic factors, Dr. Sampson hopes to link how insecticides trigger these defects of the intestinal tract and trigger Parkinson’s symptoms.

“Going back 200 years to James Parkinson’s first description of the disease, he noted that individuals with the shaking palsy also had dysfunction in their gut,” said Dr. Sampson. “As the field grew to understand the complexity of gut to brain communication and the role of the indigenous microbiome in this communication, it was clear that this path might be involved in neurological diseases, such as PD.”

Exposure to pesticides is a leading environmental risk for many neurological diseases, including Parkinson’s disease. Symptoms in the gut, including constipation and inflammatory bowel disease, often occur before developing Parkinson’s motor symptoms.

The gut microbiome is one of the first parts of the body to interact with oral exposures, for instance, through eating foods with residual pesticides. However, little is known about how the gut and its microbiome respond to insecticides, and how these changes may specifically impact Parkinson’s.”

“We know that PD likely arises from a confluence of genetic and environmental factors,” said Dr. Sampson. “Our study hopes to better understand the etiology of PD by exploring the contributions of the gut microbiome to chemical exposures that trigger PD-like pathology. We hope that this will provide insight at the earliest stages of the disease to better prevent PD and develop new therapeutic targets.”

2021 Stanley Fahn Junior Faculty Award  

Exploring Brain Chemicals’ Role in Parkinson’s Cognitive Decline

Scott Owen, PhD, of Stanford University, received a Parkinson’s Foundation Stanley Fahn Junior Faculty Award to study, understand and restore cognitive function in mouse models of Parkinson’s disease (PD). These findings could lead to more effective, targeted treatments for PD.

Many people with Parkinson’s not only experience loss of motor function and slowing of movement, but also experience cognitive changes including impulsive behavior and reduced capacity for flexible learning — the ability to adapt to a changing environment. While pharmacological and surgical treatments can be effective for treating motor symptoms, there is a critical need for better treatments for cognitive symptoms.

“Changes in cognitive function are comparatively poorly understood, but can be life-changing and debilitating,” said Dr. Owen. “By investigating mechanisms underlying these changes using mouse models, and how these mechanisms respond to common treatments including Levodopa and deep brain stimulation, our goal is to build a fundamental understanding of the underlying biology that can be used to modify, develop and innovate future treatments that are tailored to improve cognitive function.”

Research suggests Parkinson’s symptoms arise from an imbalance between two key brain chemicals, dopamine and acetylcholine. Elevated levels of acetylcholine are essential for flexible learning in the healthy brain, but it is not known whether or how disruption of the relationship between dopamine and acetylcholine contributes to the deficits that are observed in Parkinson’s.

Dr. Owen will investigate where and how acetylcholine acts in the brain to facilitate flexible learning, and how this pathway is altered following the loss of dopamine.

“New tools are emerging and driving discovery in neuroscience at an accelerating rate, making this a particularly exciting time to be in the field,” said Dr. Owen. “Multiple innovations are on the horizon targeting all aspects of Parkinson’s disease from diverse standpoints. I am exceptionally enthusiastic about the potential of this work for guiding future treatments of Parkinson’s and gaining a deeper understanding of brain function.”

Of his grant award, Dr. Owen said, “The award from the Parkinson’s Foundation is an absolutely invaluable jump-start for this project. In addition to directly supporting a specific project, this early funding can have a “multiplier” effect by establishing the foundation for a sustained, large-scale effort focused on Parkinson’s research in my lab in the future. Building on the support from the Parkinson’s Foundation, I anticipate that this work will be a core focus of my lab for many years.”

2021 Stanley Fahn Junior Faculty Award  

Protecting Midbrain Neurons to Delay or Treat Parkinson’s

Lindsay Mitchell De Biase, PhD, from the University of California, Los Angeles, received a Parkinson’s Foundation Stanley Fahn Junior Faculty Award to gain a better understanding of the role of central nervous system immune cells called microglia in Parkinson’s disease (PD). Ultimately, this work could lead to therapies that delay or treat Parkinson’s.

Microglial cells can shape neuron function and health and remove debris from surrounding tissue. They regulate the signaling connections between neurons (called synapses). They also regulate central nervous system inflammation. Previous research suggests structures within the cell called mitochondria may be able to regulate the function of midbrain microglia and their responses to aging.

“Many gene mutations that increase the risk for Parkinson’s are mutations in genes related to mitochondrial function,” said Dr. De Biase. “We think that some of these mutations are increasing disease risk, not only by affecting energy production within neurons but by pushing microglial into a damaging, inflammatory state.”

Dr. De Biase’s goal is to determine if manipulating the function of microglia can protect midbrain dopamine (DA) neurons, which regulate movement and play an important role in the progression of PD. Currently, there is no way to protect these brain cells.;

“Microglia are dynamic, malleable cells and could represent therapeutic targets that are highly distinct from many that have been explored thus far,” said Dr. De Biase.

Microglia are different in the midbrain compared with other brain regions, Dr. De Biase discovered. During aging, they multiply. They release inflammatory factors earlier than microglia in other brain regions. This creates early “pockets” of inflammation that are likely to interfere with synapse function and neuron health.

These findings suggest that the unique traits of midbrain microglia are key to making DA neurons more vulnerable to Parkinson’s. Discovering what makes these microglia more responsive to aging and disease holds great promise for harnessing these cells to protect DA neurons.

Using new technology, Dr. De Biase will seek to better understand the role of microglial mitochondria in a mouse model of Parkinson’s disease. The intervention strategy she develops could be used in people who are at high risk for developing the disease, to delay or prevent disease onset. In people with PD, it could be used to create a more neuroprotective environment, preserve remaining dopamine neurons, and hopefully, delay disease progression.

Dr. De Biase has taken inspiration in her work from her father, a retired physician, who at times expressed frustration about the limits to what treatments he could offer and was envious of researchers who work to advance scientific knowledge.

“I have always hoped that my research efforts can benefit human health,” Dr. De Biase said. “We clearly need both clinicians and researchers. Even if I can’t meet with patients directly in a consultation room, I am hoping that our research can go on to help numerous people out there who each have their unique stories and struggles with the disease.”

Of the Parkinson’s Foundation grant, Dr. De Biase said, “This award has been absolutely instrumental in giving us the support to pursue these studies. I am a relative newcomer to the field of Parkinson’s research. This award will help us secure additional funding to continue pushing forward in this research direction. Interacting with other researchers and individuals living with PD through the Foundation is also enormously beneficial to our efforts.”

2021 Postdoctoral Fellowship 

Solving Sleep Problems Related to Parkinson’s

Daniel Silverman, PhD, of the University of California, Berkeley, received a Parkinson’s Foundation James R. "Jim Bob" Moffett, Sr. Postdoctoral Fellowship grant to study the mechanisms that contribute to sleep disturbances in Parkinson’s disease (PD). This could lead to innovative treatments or preventative measures to improve this common side effect of PD.

Sleep problems sometimes act as an early warning sign of PD before movement deficits set in and may severely impair quality of life.

Sleep can also be negatively impacted by medications that treat other Parkinson’s symptoms, which affect levels of brain chemicals called dopamine and norepinephrine. Brain nerve cells (or neurons) that release these chemicals are also involved in regulating sleep and are among the first neurons to deteriorate in Parkinson’s. The relationship between sleep problems and nerve cell degeneration is not well understood.

Dr. Silverman, who developed novel approaches for revealing the mechanism of retinal degeneration and night blindness from a rhodopsin (light-sensitive receptor protein) mutation in graduate school, was drawn to Parkinson’s research based on the work of Berkeley neuroscientist Yang Dan, PhD.

“After seeing Dr. Dan’s research on sleep, I became curious — often thinking about sleep experiments lying awake at night,” said Dr. Silverman. “It was striking to learn that little is known about the mechanisms that control the brain’s balance between wakefulness and sleep, especially because disruption is a common symptom of Parkinson’s disease.”

Dr. Silverman will focus on the role of molecules called reactive oxygen species (ROS) in PD sleep problems. Emerging evidence has shown that reactive oxygen species build up when neurons release dopamine and norepinephrine. Research also shows these neurons are inhibited by high levels of ROS.

Using a mouse model, Dr. Silverman will try to determine if ROS levels grow during long periods of being awake and whether quality sleep may help cells to recover from the stress caused by ROS. “With a better understanding of the molecular dysregulation that underlies sleep disturbances in Parkinson’s, a targeted treatment could one day aim to restore healthy sleep,” said Dr. Silverman.