2024 Impact Award 

Resisting Parkinson’s Disease through Restoring Mitochondria Recycling  

The ability of a cell to recycle its defective parts is crucial for it to remain healthy and functional. This is especially true for neurons, which have some of the most complex processes to manage in the body and little room for inefficiency. In certain forms of Parkinson’s disease (PD), proteins involved in those critical recycling processes are damaged, which is believed to cause affected neurons to break down over time.  

Daniel Finley, PhD, a recipient of a Parkinson’s Foundation Impact Award, believes that he and his co-investigator Elena Ziviani, PhD, have found a “backup” compound that could fill in and restore neurons’ recycling abilities. With sufficient research and experimentation, this compound could become a new treatment that slows or prevents PD progression. 

Cells require a consistent and efficient supply of energy to function properly. This is provided by mitochondria, cellular powerhouses that turn oxygen into renewable chemical energy. Over time, these powerhouses wear down and eventually need to be recycled so that new mitochondria can be made.  

A protein called Parkin plays a major role in defective mitochondria recycling, and PD-linked mutations have been discovered that cause Parkin to become nonfunctional (in fact, the name “Parkin” comes from its discovery through PD research). Without functional Parkin, defective mitochondria clog up neurons and lead to their degeneration. 

In summary, healthy neurons rely on their ability to recycle defective parts, but in Parkinson’s, mutations in the Parkin protein hinder this process, leading to degeneration. Drs. Finley and Ziviani have identified a potential alternative way to stimulate the recycling function, which can potentially lead to new treatments. 

Recent experiments conducted by Dr. Ziviani have revealed that a compound they discovered, called IU1, can enhance an alternative mitochondria recycling process in neurons with dysfunctional Parkin. Additional chemistry led to the discovery of an IU1 variant, called IU1-366, that works even better. Next, the lab will test how it works in mice to ensure its safety and effectiveness for future human trials. 

From his lab at Harvard Medical School in Boston, MA, Dr. Finley will first administer IU1-366 to mice and measure how that changes mitochondria upkeep in brain neurons.  

Then, he will use mice genetically modified to have dysfunctional Parkin, simulating PD, to see if IU1-366 can overcome the disease-related mitochondria recycling issues. Across all mouse experiments, Dr. Finley will also monitor how IU1-366 affects the animals’ general health, assessing whether the treatment has side effects.  

Finally, Dr. Ziviani will delve deeper into the biochemistry of IU1-366 using neurons in petri dishes, looking to better understand the mechanisms behind how the compound works to guide future therapeutic improvements. 

These studies will determine if IU1-366 could be a future treatment for people with Parkin-affected PD, opening a potential new option that may slow disease progression.  

Speaking on the merit of his upcoming research, Dr. Finley said, “With this award, we will be able to assess more deeply, using a mouse model, whether IU1-366, or a closely related compound, could have therapeutic benefit in humans. We are very excited to move this work forward and are hopeful for interesting results.” 

Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers. 

2024 Impact Award 

Exploring DNA “Safety Caps” as a Potential Source of Neuron Loss in Parkinson’s 

The biological hallmark of Parkinson’s disease (PD) is a progressive loss of neurons in the brain, particularly ones that produce the neurotransmitter dopamine. What makes these neurons uniquely vulnerable to malfunction has been a major subject of research, as understanding their weaknesses could lead to new treatments that protect them from failing.  

Oxidative damage (where chemically reactive forms of oxygen molecules cause disruptions in cells) has been linked to PD-associated dopamine neuron loss. However, we still don’t know exactly how reactive oxygen molecules lead to the death of neurons.  

Edward Burton, MD, PhD, and recipient of a Parkinson’s Foundation Impact Award, believes the answer may lie with telomeres, the protective “caps” on chromosomes linked to aging. This is one of the most detailed studies to date on the role of telomere damage in PD. 

What is a telomere?

Telomeres are the long stretches of repeating DNA patterns found at the ends of chromosomes. They act as a "safety cap," protecting chromosome ends from deteriorating or being inappropriately recognized as areas of DNA damage. This is one of the first studies to link telomeres to Parkinson's disease.

Cells need a way to keep the delicate ends of their DNA protected from deteriorating or being incorrectly recognized as areas of DNA damage. The solution to that problem is telomeres, the long stretches of repeating DNA patterns found at the ends of chromosomes. These patterns protect chromosome ends, but get progressively shorter every time a cell divides, limiting the lifespan of cells that routinely divide, such as skin, blood and intestinal cells, and contributing to aging. 

The importance of telomeres in neurons has not been well investigated, mainly because neurons do not divide once established and therefore their health and lifespan should not be limited by telomere shortening.  

Dr. Burton and collaborators from their labs at the University of Pittsburgh in Pennsylvania, have recently discovered that another mechanism may link faulty telomeres to PD. While neurons may not show telomere shortening as a result of cell division, damage to their telomeres — particularly oxidative damage already linked to PD — could still trigger emergency DNA damage responses that impair neuronal function and eventually cause cell death. 

“This is an exciting new research area in response to several recent discoveries about telomere biology and its role in the aging brain” - Dr. Burton 

To test his hypothesis, Dr. Burton will first take postmortem brain tissue samples from people who had PD and investigate if their dopamine neurons had signs of oxidatively-damaged telomeres. This will tell him if he’s on the right track with his theory that damaged telomeres are associated with PD.  

For the next part of his research, Dr. Burton will use genetically modified zebrafish, in which he can trigger oxidative damage in neurons on demand using a technique called chemoptogenetics. By specifically causing oxidative damage in dopamine neurons, he will be able to see if the neurons’ telomeres are impacted and lead to a DNA damage response that could harm the cells.  

Ultimately, Dr. Burton will generate a special genetically modified zebrafish model that allows him to  damage the neuron telomeres directly and specifically, further investigating if telomere damage could be the reason that dopamine neurons die in PD. 

How does studying fish help further Parkinson’s research? 

Zebrafish share more than 70% of the same DNA as humans. They are a widely used animal model for neuroscience research. They are useful and effective for experiments for many reasons: 

• Their brain and nervous systems are functionally similar to humans, including the utilization of dopamine neurons. 

• They have telomeres similar to humans. 

• Genetic modifications can create zebrafish with transparent skin, allowing their brains to be studied directly under a microscope in an intact living animal. 

By exploring this innovative telomere-linked mechanism behind neuron loss in PD, Dr. Burton hopes to set the foundation for future therapies and treatments that bolster telomeres to help protect dopamine neurons and prevent disease progression.  

Speaking on his upcoming research, Dr. Burton said “This award provides a unique opportunity to develop a new collaborative program that we hope will help understand why brains cells malfunction and die in PD. As a clinician caring for patients with PD, this is an important goal, as it may eventually help us develop treatments that slow disease progression.” 

Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers. 

2024 Impact Award 

Creating Virtual Brains to Study how Parkinson’s Disease and Depression Interact 

One of the most common non-movement symptoms experienced by people with Parkinson’s disease (PD) is depression. While the mental health impacts of PD-associated depression are debilitating on their own, they have also been associated with increased PD severity. This implies that the neurological changes in the brain that cause depression may also affect the progression of PD. Therefore, better understanding this overlap could improve treatment strategies for people with both.  

Henricus Ruhe, MD, PhD, and recipient of a Parkinson’s Foundation Impact Award, will be using sophisticated brain mapping technology to investigate this subject, seeking new ways to personalize treatments for those with depression and PD.  

For this research, he will collaborate closely with Morten L. Kringelbach, PhD, from Oxford University and Gustavo Deco, PhD, from Pompeu Fabra University in Barcelona, who developed the techniques.  

Dr. Ruhe, from his lab at the Radboud University Medical Center in Nijmegen, Netherlands, a Parkinson’s Foundation Center of Excellence, plans to utilize a new neuroscience research tool called whole-brain computational modeling. The science and math involved with this tool is complex, but put simply, this technique allows researchers to take data from a person’s MRI scans and create a digital model of their brain.  

Within each of these models are nodes, small brain areas whose neurons seem to generally activate together. Based on blood flow measured with MRI-data, the interaction patterns between nodes are mapped and measured to track how signaling information flows through the brain. Additional data, such as physical anatomical distances in the brain, will also be used to bolster the models. 

Using previously collected clinical MRI data from people with PD, some with and some without depression, Dr. Ruhe will be able to generate brain models for his testing. By analyzing and comparing them, he hopes to identify how information flow in the brain is altered by depression in PD contexts.  

In addition, in another cohort of PD-patients without and with depression, where MRI scans taken without (OFF) and with (ON) the use of levodopa medication will provide valuable information about how PD treatment affects depressed and non-depressed brains differently. 

These established brain models can then be used to conduct in silico experiments — meaning that instead of working with cells in petri dishes (in vitro) or with live animals (in vivo), the testing is done with computer simulations.  

In these simulations, Dr. Ruhe will aim to modify specific nodes and see how the rest of the brain reacts and reorganizes in response. These disruptions can be designed to mimic medications, estimating how they would work in the brains of people with and without PD-linked depression.  

Performing these perturbations across the different PD brain models and comparing the outcomes will provide: 

• Major insights into which regions are most critical to brain function in PD and depression. 

• What therapies potentially work best for people with PD and depression, improving the scope and effectiveness of personalized treatments in the future.  

Speaking on the importance of this award for his research goals, Dr. Ruhe said, “I am honored to have received this prestigious award. This will help our team and the Parkinson’s community to develop whole-brain models to better understand and preferably modify non-motor symptoms in PD. This will have substantial impact on selections of treatment of depression in PD patients by identifying susceptible brain regions for different forms of treatment.” 

Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers. 

2024 Postdoctoral Fellowship 

Charting Brain Wave Changes to Help Treat Levodopa-induced Movement Symptoms 

The dopamine-replacement medication levodopa is used by a majority of people with Parkinson’s disease (PD) to help treat the hallmark movement disorder symptoms. While this routine treatment often provides quality-of-life improvement, continuous use of levodopa can lead to new movement symptoms called levodopa-induced dyskinesia (LID).  

It is estimated that more than half of people who take levodopa for their PD symptoms develop LID, but the neurological reasons behind this phenomenon are still not well understood. 

Jeroen Habets, MD, PhD, and recipient of a Parkinson’s Foundation Postdoctoral Fellowship, seeks to identify brain wave “biomarkers” of LID, highlighting regions of the brain that go awry during LID and could be targeted by magnetic stimulation therapy to reduce or eliminate LID completely. 

The rhythmic patterns of neuron activation in the brain used to achieve tasks like movement, memory recall and much more can be observed and measured as brain waves. Different frequencies — the speed and intensity of the patterns — of brain waves are associated with different mental states and activities, such as the slow, calm delta waves of deep sleep or rapid, intense gamma waves of alertness and agitation. 

Using a machine called a magneto-encephalograph, Dr. Habets will take study participants with PD and visualize the brain wave activity that occurs during bouts of LID.  

By measuring each participant’s normal brain waves patterns and seeing how and where they change during LID, Dr. Habets hopes to find regions that could be targeted for treatment using non-invasive transcranial magnetic stimulation (TMS), which involves using guided magnetic waves to affect brain wave activity.  

Knowing what regions of the brain and which frequencies of brain waves are involved with LID could lead to personalized TMS treatments that alleviate those debilitating levodopa side effects. 

From the lab of Andrea Kühn, MD, at the Charité University Hospital in Berlin, Germany, Dr. Habets is eager to begin his proposed research with the support of the Parkinson’s Foundation fellowship.  

“This work will lead to a better understanding of how dyskinesia develops, and what happens in the upper layers of the brain when people suffer from involuntary dyskinetic movements,” said Dr. Habets. “Besides extending our fundamental knowledge, these findings will help to develop brain stimulation strategies to treat dyskinesia. Potentially, this work will extend our future therapeutic possibilities to help people with Parkinson's disease that suffer from dyskinesia.” 

Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers. 

2024 Impact Award 

Searching for Gut Bacteria That May Lead to Parkinson’s Disease 

Research has shown that the trillions of bacteria that live in our gut have incredible influence over our health — offering protection from many illnesses and diseases. Recent studies suggest that alterations in gut bacteria may drive the development or progression of  Parkinson’s disease (PD).  

Gut bacteria have been linked to PD development in different ways, like driving the accumulation of misfolded proteins or even inhibiting the effectiveness of PD medication. However, identifying the specific types, or strains, of bacteria most linked to PD and understanding what attributes they possess to propel the disease has been a daunting challenge for scientists.  

Chris Smillie, PhD, the recipient of a Parkinson’s Foundation Impact Award, is using cutting-edge genetic tools and techniques to comb through trillions of bacterial cells to find the ones most associated with PD. Through his research, he aims to identify how their activity and function may contribute to the disease, and how we might be able to target gut bacteria to slow, stop or prevent PD progression. 

Gut bacteria are highly adaptable microbes, capable of rapid evolution in response to changes in their environment. “Health-adapted” bacteria strains, which thrive in a healthy gut, might offer a protective benefit for the person they live in by fighting off viruses or other invaders. Conversely, “illness-adapted” strains may thrive in environments of gastrointestinal distress, potentially evolving to cause and maintain such distress.  

Following the growing evidence pointing toward gut bacteria affecting PD, Dr. Smillie believes that there are “PD-adapted” bacteria strains that adapt to and consequently cause conditions that progress PD. 

To figure out which bacteria might be PD-adapted, Dr. Smillie and his research team at the Massachusetts General Hospital in Boston, MA, a Parkinson’s Foundation Center of Excellence, will utilize stool samples from nearly 3,000 study participants: some with PD, some without PD as controls, and others with inflammatory bowel diseases (to isolate PD-adaptation from other gut-distressing adaptations).  

After analyzing all the bacterial DNA from these samples, he will use computational tools to find the different strains present as well as map which unique strains are most associated with PD.  

Going further, Dr. Smillie plans to untangle the PD-adapted strains’ evolutionary paths, discovering which genetic changes they underwent over time to become associated with PD. Identifying these changes will also help him understand the functional connections between the strains and PD, uncovering mutations in bacterial proteins that may contribute to disease progression. 

After amassing this staggering amount of genetic data about PD-adapted bacteria, Dr. Smillie hopes his research will provide scientists and doctors with new ways to diagnose and treat PD earlier, by looking at the gut instead of the brain.  

On receiving this award and the impact of his proposed research, Dr. Smillie said “The Parkinson's Foundation Impact Award is an immense honor. With this award my lab will apply powerful computational tools to identify the bacteria that are associated with Parkinson's, which will yield new insights into disease mechanisms, and may guide the development of microbiome-based therapeutics to treat the disease or its gut symptoms.” 

Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers. 

2024 Impact Award 

Exploring Gut Health Biomarkers as Early Indicators for Parkinson’s  

The ability to identify Parkinson’s disease (PD) in people before the onset of progressing movement and cognitive changes is a major goal of PD research. Through retrospective studies, some early symptoms have been routinely noted in people years prior to their PD diagnoses, making them potential flags for catching the disease sooner. Gastroparesis, which consists of bloating and nausea, is an example of a symptom experienced earlier in life by a large majority of those with PD. However, this condition is also common amongst people who never develop PD, making it difficult to use as a reliable PD indicator without more data.  

Trisha Pasricha, MD, and recipient of a Parkinson’s Foundation Impact Award, aims to compare the gut biology of those with and without PD using innovative new technology, to discover the biomarkers of PD-linked gastroparesis that will improve future diagnoses. 

Previous research into the active biology of the gut has been limited due to the difficulty in collecting useful tissue samples from live donors. Fortunately, recent technological advances in biopsy collection tools now allow researchers like Dr. Pasricha to safely obtain “full-thickness” gut tissue samples with more deeper layers of the gut wall for study.  

From her lab at the Beth Israel Deaconess Medical Center in Boston, MA, a Parkinson’s Foundation Center of Excellence, Dr. Pasricha will analyze the gastric biology of full-thickness gut tissue samples collected from: 

• People with PD in all stages 

• People with gastroparesis, without PD  

• People without either condition  

Each layer of the gut wall consists of a diverse mix of muscle, connective tissue, neurons and immune cells. Dr. Pasricha, using a wide range of measurement tools and techniques, will investigate which cell types in which layers are most differentially impacted in PD gastroparesis compared to non-PD gastroparesis. The goal of these comparisons is to highlight potential gut biomarkers that will allow future physicians to spot PD earlier from initial gastrointestinal issues.  

She will also compare these biomarker results to clinical assessments from the tissue donors with PD, looking for correlations between gut health and disease severity to further explore the link between the two. 

As a clinician working directly with people with PD experiencing gastrointestinal issues, Dr. Pasricha is inspired to receive the Parkinson’s Foundation grant and motivated to begin this translational research.  

“I have met countless patients living with Parkinson's who seek my help treating their gastrointestinal symptoms,” she said. “I am grateful that because of this award I will be able share with my patients that I am part of the community of scientists working to address the bigger unmet needs of patients like themselves. These findings may be leveraged toward establishing future gastrointestinal biomarkers or therapeutic targets to help alleviate those suffering from this disease.” 

Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers. 

2024 Impact Award 

Exploring a Unique Genetic Risk Factor for Parkinson’s in Black and African American Populations 

Along with aging and environmental factors, genetics is one of the three major factors involved in the development and progression of Parkinson’s disease (PD). Ongoing research aims to find disease-associated gene mutations to better understand PD and how to prevent or treat it. While many critical discoveries have been made from such studies, it is important to note that the research to date has been predominantly conducted using genetic samples from those of European ancestries, leaving a gap of scientific knowledge for those people with PD of other ancestries.  

Henry Houlden, PhD, a recipient of a Parkinson’s Foundation Impact Award, will be expanding the diversity of our genetic understanding of PD by studying a newly discovered disease-associated mutation found nearly exclusively in African American and African-admixed (people of African heritage outside of Africa) populations through a fruitful partnership with Professor Njideka Ulunma Okubadejo, MBCHB, MD, FMCP, FAAN, and her team in Lagos, Nigeria, and colleagues at the National Institutes of Health in Bethesda, MD. 

The mutation in question was found when Dr. Houlden and colleagues previously performed a genome-wide association study with DNA samples from nearly 200,000 people of African American and African-admixed ancestry, approximately 1,500 of whom have PD. This type of study analyzes the entirety of each person’s DNA and highlights similarities and differences between the genes of those with and without the disease, offering potential genetic clues as to which mutations are linked to PD.  

One of the clues Dr. Houlden found was a PD-linked mutation in the DNA region that helps make an enzyme called GCase (glucocerebrosidase). While PD-linked mutations in this region have previously been found, this mutation seems to affect how the enzyme works in ways that have not been observed before in similar, European ancestry-related mutations. 

To better understand how this mutation may lead to PD, Dr. Houlden will measure various genetic and biochemical factors related to GCase in 72 blood and tissue samples from people of African American and African-admixed ancestry with and without PD. He will also use parts of those samples to create petri-dish neurons of these donors, allowing him (and future researchers) to more effectively investigate how the mutation may drive the development of PD.  

From these experiments, Dr. Houlden will generate valuable data advancing our understanding of this African-ancestry PD risk factor and contribute to new PD treatments for these underrepresented populations. 

From his lab in the University College London Institute of Neurology in the United Kingdom, Dr. Houlden is ready to continue his impactful research through Parkinson’s Foundation grant funding.  

“I am very interested in Parkinson's disease in diverse populations I think this is a major link that is missing in our research strategy and will bring significant findings important to PD across the world,” he said. “The award will also exemplify how foundations around the world, such as the Parkinson's Foundation, are funding global research and understand the need to investigate and form partnerships with diverse populations for research.” 

Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers. 

2024 Postdoctoral Fellowship 

Exploring and Unlocking Motor Memory in Parkinson’s 

Despite how simple daily movements like walking, using utensils, or riding a bike may seem, they require the precise and instantaneous activation of complex networks of neurons. As we learn to perform these types of movements, the brain stores these neuronal activation patterns, allowing us to utilize them seamlessly in the future, making the movements feel effortless. For people with Parkinson’s disease (PD), that effortlessness diminishes as common PD symptoms make even simple movements challenging. 

Fuu-Jiun Hwang, PhD, recipient of a Parkinson’s Foundation Postdoctoral Fellowship, aims to discover whether those motor memories are still present in the brain but have become inaccessible in PD, and if so, how they can be reactivated. 

The scientific term for how the brain “memorizes” physical actions is motor learning. This process results in the formation of motor memory engrams, which are the specific activation patterns and timing of neurons needed to perform a memorized action. 

Motor memory engrams are like songs played by an orchestra. Specific musicians (neurons) must play the right notes in the right order (activation patterns) to perform the song. After enough practice, when the conductor asks the orchestra to play a certain song (a movement), they know exactly what to do (effortless engram utilization). 

Dr. Hwang, working in the lab of Jun Ding at Stanford University, will use advanced neurochemical tools in mouse brains to visualize and map the motor memory engrams associated with a forelimb-reaching task, a well-established motor learning behavior task in mice. He will then induce PD-like brain disruption in the mice and observe whether the same engrams activate when the mice perform the learned task, or if the disease alters the neuron patterns involved. Additionally, Dr. Hwang will explore whether administering levodopa — the most potent PD medication — can restore the original engrams altered by the disease. 

Previous neuroscience research has shown that repeated practice and performance of actions rewires the brain to reinforce and improve the associated motor memory engram, a phenomenon known as synaptic plasticity. Dr. Hwang plans to take his experimental model further to examine whether synaptic plasticity associated with the motor engram is also impacted by PD. 

The discoveries from these experiments will help Dr. Hwang and other PD neuroscientists better understand how motor memory and learning are affected by Parkinson’s disease, and what potential treatments could be developed to address movement symptoms at their source. 

Reflecting on the significance of the Parkinson’s Foundation grant, Dr. Hwang said, “Receiving this award is crucial for supporting my research on motor engrams and their application to Parkinson’s disease. Ultimately, this award will help me contribute to the understanding of PD and develop novel therapeutic strategies, potentially improving the lives of individuals affected by this debilitating disease.” 

Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers.