2023 Impact Award  

Exploring New Types of Parkinson's-affected Neurons to Expand Treatment Opportunities

In Parkinson’s disease (PD), dopamine-releasing neurons in the brain region called the substantia nigra break down over time. These neurons play important roles in regulating the activity of other neurons in the motor region of the cerebral cortex, so their progressive loss leads to the movement symptoms seen in the disease. While a great deal of PD research has looked into the disease’s impact on the basal ganglia, less is known about the cellular changes that happen to the motor cortex. To better understand these downstream neurological effects and how to better treat or prevent them clinically, Hong-yuan Chu, PhD, recipient of a Parkinson’s Foundation 2023 Bill and Amy Gurley Impact Award, will be doing a deep-dive into the chemical and functional changes that occur in motor cortex neurons after substantia nigra dopamine neurons are lost.

From his lab at the Van Andel Research Institute in Grand Rapids, Michigan, Dr. Chu has identified a specific type of neuron in the motor cortex called parvalbumin-expression interneurons (PV-INs) that seem to become more sensitive and overreactive after PD-like dopamine neuron loss. Using mouse models, Dr. Chu and his team will use sophisticated electrophysiology recording techniques to measure how differently PV-INs act in PD and non-PD contexts.

With a better understanding of how PV-INs change during PD progression, Dr. Chu will next test how well those neurons interact with other neurons with and without dopamine neurons present. PV-INs primarily communicate with pyramidal tract neurons (PTNs), which relay signals to the spinal cord that get forwarded to muscles for movement. With powerful microscopes, Dr. Chu will be able to see how PV-INs organize themselves around PTNs to help facilitate motor signaling, comparing their effectiveness in mice with and without PD-like dopamine neuron loss.

Completing this research will provide exciting new data on a relatively understudied type of neuron in the context of PD. Through these experiments, Dr. Chu hopes to find new targets for treatment in the brain, opening up additional therapeutic options in the future. After learning that he had received this award, Dr. Chu said: “I am grateful for the support of the Parkinson’s Foundation, which will help my lab pursue new ideas and accelerate expansion of our research program. This work has great potential to provide new insights into how Parkinson’s affects brain function, which can help us design better treatments in the future.”

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2023 Impact Award  

Utilizing a Molecular Switch to Correct Disruptive Parkinson's Disease Protein Clumps

Research has shown that a protein called alpha-synuclein is likely a key driver of Parkinson’s disease (PD) progression. If the regulation of alpha-synuclein is out of balance in the brain, it can cause major stress to neurons and lead to their breakdown, a hallmark sign of PD. While most studies have focused on how alpha-synuclein goes haywire in PD, Jane Aldrich, PhD, recipient of a Parkinson’s Foundation 2023 Bill and Amy Gurley Impact Award, is taking a different approach: she will be investigating how to improve the neurons’ ability to regulate alpha-synuclein and thereby stop cellular damage.

Proteins are used to perform the tasks and processes that keep everything running smoothly inside cells. Some proteins, like alpha-synuclein, are chemically modified in the cell by attaching a small group at specific locations which can change their behavior. In PD, when alpha-synuclein is modified it forms toxic threads in neurons, which eventually form clumps. There is a separate protein, called PP2A, whose job is to take the chemical group off alpha-synuclein. However, in many PD cases, this protein doesn’t work properly, potentially leading to the accumulation of clumped, chemically modified alpha-synuclein protein.

In her lab at the University of Florida, Dr. Aldrich has identified a small molecule that can repair PP2A in cells. A functioning PP2A can restore the regulation of alpha-synuclein, preventing PD-associated damage. In collaboration with Dr. Paramita Chakrabarty, Dr. Aldrich will use a mouse model of alpha-synuclein dysregulation and inject the mice with this small molecule that can potentially restore the function of PP2A. After treating mice for up to two months, they will look at brain tissue samples under a microscope to see if this molecule was able to prevent alpha-synuclein from clumping inside neurons.

Next, Dr. Aldrich will test variations of the PP2A repair molecule, looking for versions that might work better than the original. As with all new drugs or treatments, even slight molecular changes can lead to improved function and outcomes. By doing these experiments, Dr. Aldrich hopes to find better PP2A repair molecules and advance these compounds for potential future therapeutic use.

When asked about what this award and support means to her, Dr. Aldrich replied, “I am very excited that research from my lab could possibly help identify disease-modifying therapies for Parkinson’s disease. I have a long-standing interest in exploring compounds that are active in the brain, and this will be the first opportunity for my lab to expand our research to target a neurodegenerative disease. The proposed research will provide proof of concept that compounds we synthesize can modulate the state of alpha-synuclein in PD models and have potential application as treatments for the disease.”

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2023 Impact Award  

Overcoming Communication Barriers and Improving Well-being with Listener Training

Most people know about the movement symptoms of Parkinson’s disease (PD), but they do not usually think about how the disease impacts communication. Research shows that up to 90% of people with PD may develop hypokinetic dysarthria, a disorder that affects a person’s physical speaking ability. This disorder contributes to decreased intelligibility of those affected, greatly impacting their ability to communicate with others. Common interventions focus solely on the patient (speaker) to improve their speech. Kaitlin Lansford, PhD, recipient of a Parkinson’s Foundation 2023 Bill and Amy Gurley Impact Award, seeks to improve the social well-being of those with PD experiencing this speech disorder by investigating whether listening training for their care partners can help overcome these communication barriers.

The two main speech consequences of hypokinetic dysarthria are reduced volume and imprecise articulation. Therefore, speech therapy for those with hypokinetic dysarthria is often focused on having the person speak louder and more clearly. Such speaker-targeted interventions can improve intelligibility, but its effectiveness is limited, especially when related physical and cognitive symptoms are more severe. Dr. Lansford, director of the Motor Speech Disorders lab at Florida State University, in collaboration with her research partner, Dr. Stephanie Borrie from Utah State University, has demonstrated that listeners can be trained to better understand dysarthric speech. Such listener-based interventions have the potential to improve communication without increasing the communicative burden of the person with PD. With care partners often wanting to have a more active role in the rehabilitation of their loved ones, listening training has great potential for improving the social lives of those with PD.

To better understand how listening training can be used to complement commonly used speaker interventions for those with PD-associated hypokinetic dysarthria, Dr. Lansford will conduct a study in which 20 speakers with PD and hypokinetic dysarthria and 600 listeners will be recruited to participate in a series of speaking and sensory tasks. The speakers will provide speech samples and will be cued to speak, louder, more clearly or in their normal speaking voice. The speech samples will be used to generate perceptual experiments. The recruited listeners will be randomly assigned to one of the speaker training conditions and half (300) will engage in listening training, in which they will benefit from a familiarization experience with feedback. The other half of listeners (300) will not receive listening training. All listeners will transcribe the speech samples and these transcriptions across the different speaker and listener training conditions will be scored for intelligibility, after which the impact of combined training can be properly assessed.

“Receiving the Parkinson's Foundation Impact Award to support this research project is a true honor,” said Dr. Lansford. “Given that most daily communication for people over 65 years occurs with family and friends, a dual [speaker and listener] treatment approach has the potential to significantly and positively impact the lives of people with PD and their key communication partners. [This award] will greatly enhance the visibility and impact of our findings, opening doors to future collaborations, grants, and opportunities to support this line of research, thereby advancing therapeutic interventions and enhancing patient care in PD.”

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2023 Impact Award  

Controlling Brain Inflammation to Reduce Collateral Damage in Parkinson's Disease

Inflammation is the body’s way of dealing with injury or foreign organisms, such as bacteria or viruses. While effective, the inflammatory process can cause collateral damage to cells and tissues if not managed appropriately. As the body ages, the risk of chronic inflammation — when the inflammatory alarm stays on even when is no threat — increases. Chronic inflammation in the brain has been observed in Parkinson’s disease (PD), and the associated damage likely contributes to the progressive loss of dopamine neurons that characterize the disease. Ray Norton, PhD, recipient of a Parkinson’s Foundation 2023 Bill and Amy Gurley Impact Award, believes that PD-induced inflammation involves brain cells called microglia, and he has a plan for how to inhibit those brain cells to reduce inflammation and potentially slow down disease progression.

In healthy brains, microglia release chemical signals —called cytokines— that turn on the inflammation alarm when facing a threat. This recruits immune cells to deal with the threat, after which the microglia stop releasing inflammation cytokines and the alarm turns off. In PD, microglia can malfunction in ways that make them release those cytokines inappropriately and in greater amounts, triggering inflammatory responses that can damage and ultimately break down sensitive neurons. Prof. Norton, from his lab at Monash University in Melbourne, Australia, has developed a peptide that binds to a specific protein on the microglia, which is over-active in PD, leading to cytokine release and neuron death. The peptide developed by Prof. Norton has the ability to bind to this protein and inhibit (i.e., block) its function, thus preventing the release of those inflammatory cytokines and subsequent neuron damage that occurs in PD.

Prof. Norton, together with his collaborators Joe Nicolazzo and Dorothy Wai at Monash, David Finkelstein at the Florey Institute of Neuroscience and Mental Health and Gyorgy Panyi at the University of Debrecen, will first be looking at how the levels of the microglial protein change in two different mice models of PD, helping them understand how those changes may contribute to increased brain inflammation. Next, he will use neurons in Petri dishes from PD and non-PD donors to assess how well his inhibitor molecule prevents the release of inflammatory cytokines in healthy and disease contexts. This will show if this inhibitor works with human microglia and could be biologically effective in the brains of those with PD. Finally, Prof. Norton will modify the design of his inhibitor molecule to make it better at crossing the body’s blood-brain barrier, a system built to protect the brain from invaders, but which can also block drugs from passing through. All these experiments will help develop this microglia inhibitor into a strong candidate for new PD therapies that reduce brain inflammation to limit and prevent neuron damage from the disease.

Prof. Norton is thrilled to have received this award to continue his work, and is excited about its potential to help those with PD: “Successful completion of this project will underpin the development of a potent and target-specific drug lead with the potential for rapid clinical translation for the treatment of Parkinson’s disease. It would be personally very rewarding to see the peptide inhibitor I developed become a clinical candidate for Parkinson’s disease.”

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2023 Impact Award  

Testing a New Way to Protect Neurons by Empowering their Mitochondria

Mitochondria are the small oxygen-consuming and energy-producing powerhouses inside cells. Evidence has shown that in Parkinson’s disease (PD), mitochondria are impaired in key groups of dopamine neurons in the brain. This impairment may contribute to the neurons’ progressive breakdown, hallmark to the disease and cause of the gradual onset of movement symptoms. Scott Waldman, MD, PhD, recipient of a Parkinson’s Foundation 2023 Bill and Amy Gurley Impact Award, has found a receptor on the surfaces of those PD-associated dopamine neurons that may provide therapeutic ways to protect the mitochondria and prevent the progression of the disease.

The receptor —called GUCY2C— was first discovered on the surfaces of cells in the intestine; there, specific hormones bind to the GUCY2C receptors and induce intestinal secretion. Drugs that mimic those hormones have been developed as treatments for constipation. GUCY2C has only recently been discovered to be on the surface of PD-relevant dopamine neurons as well, where their role seems to be linked to keeping neuronal mitochondria healthy.

Dr. Waldman, with the help of his coinvestigator Dr. Richard Smeyne at Thomas Jefferson University in Philadelphia, Pennsylvania, has already shown that genetically removing GUCY2C from dopamine neurons causes them to have smaller and less effective mitochondria, making the neurons more likely to break down. This discovery was their first clue that GUCY2C may be a useful clinical target for new PD therapies.

For his first experiment supported by this award, Dr. Waldman will take dopamine neurons from mice with and without GUCY2C receptors and treat them with a hormone-mimicking drug that activates the receptors. From this, he will be able to confidently determine if GUCY2C activation improves mitochondrial health through biochemical measurements and comparisons across the tested groups.

Next, Dr. Waldman will add alpha-synuclein protein clumps, linked to PD development and progression, to those same mouse neurons and see if GUCY2C activation protects them from the disease-causing proteins. If his hypothesis proves correct, the GUCY2C-activated neurons should be protected from PD-associated damage due to their strengthened mitochondria, while the neurons lacking the receptor will be more vulnerable. Dr. Waldman will also recreate this alpha-synuclein stress test using living mice, ultimately looking at their brains under a microscope to see whether GUCY2C activation was able to protect against PD-like neuron degeneration.

Altogether, this work will shed light on a potential new avenue for PD therapies, combating the disease by strengthening the mitochondria in the vulnerable dopamine neurons. Asked about the significance of this research support, Dr. Waldman said that this Impact Award “underscores the significance of discovering a new molecular pathway that regulates the integrity of neurons in the substantia nigra and which can be co-opted to defend against toxic insults… it represents an essential source of support to continue studies that advance these novel molecular discoveries to translation into new approaches to prevent and treat Parkinson’s disease.”

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2023 Impact Award  

Preventing Alpha-synuclein Chain Reactions with Biometrical Precision

In Parkinson’s disease (PD), a protein called alpha-synuclein clumps into microscopic fiber-like structures in the brain, known as tangled fibrils. Eventually, this leads to a chain reaction that causes more alpha-synuclein to clump, causing affected neurons in the brain to break down and spread the fibrils to neighboring neurons. Ultimately, this impairs dopamine production, which is when Parkinson’s symptoms can become noticeable. Preventing this spread of alpha-synuclein fibrils is a promising target for new PD therapies. Jingxin Wang, PhD, recipient of a Parkinson’s Foundation 2023 Bill and Amy Gurley Impact Award, is studying how reducing alpha-synuclein levels overall can make a difference in PD progression.

Recent research has shown that alpha-synuclein fibrils only cause progressive disease when there is additional, normal alpha-synuclein present. With this in mind, Dr. Wang and his team at the University of Kansas have developed a new tool to reduce alpha-synuclein levels in neurons called ribonuclease targeting chimeras (RIBOTACs).

Parkinson's & The Role of RNA

Proteins are the molecular power tools of the cell, each designed for specific jobs. Sometimes, proteins get bent or broken, causing damage.

In Parkinson’s disease, the protein alpha-synuclein breaks in a way that causes other alpha-synuclein proteins to break in a chain reaction. This happens in the brain and its damage leads to the symptoms associated with PD.

If proteins are tools, RNAs are the blueprints; RNA molecules are used to make proteins in the cell. The theory tested by this research is whether the alpha-synuclein chain reaction can be stopped by erasing all those RNA blueprints and stopping more alpha-synuclein from being made. If proven true, this intervention could ultimately be used to stop PD from spreading.

RIBOTACs are molecules with two “arms” — one that grabs alpha-synuclein RNA and another that helps break that RNA down. RNA is required for making proteins, so using this new method, RIBOTACs can reduce the amount of alpha-synuclein available, thereby preventing clumping.

Dr. Wang and his collaborator at Johns Hopkins University, Dr. Xiaobo Mao, will test the effectiveness of these RIBOTACs in mammals by injecting them into mouse neurons to measure how those RNA and protein levels are affected. A week later he will inject alpha-synuclein fibrils into the neurons to test the RIBOTACs ability to prevent the spreading and clumping of alpha-synuclein. These studies will evaluate if RIBOTACs have the potential to reduce or prevent PD progression by blocking fibril chain reactions.

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2018 Postdoctoral Fellowship
2023 Stanley Fahn Junior Faculty Award  

Connecting Environmental Exposures and Parkinson's Disease Through Accelerated Brain Aging

The greatest risk factor for Parkinson’s disease (PD) is aging, but the disease varies among affected individuals of similar ages. This implies that external factors, such as exposure to environmental toxicants, likely play a role in PD progression that coincides with the aging process. A wide range of research has been done correlating pesticide exposure to PD incidence, but the cellular processes involved in such a connection have been difficult to fully untangle. Briana De Miranda, PhD, recipient of a Parkinson’s Foundation Stanley Fahn Junior Faculty Award, will seek to better understand what happens in cells after exposure to PD-related toxicants and how that may lead to accelerated cellular aging and impact PD risk and progression.

As certain specialized cells like microglia and astrocytes age, they eventually reach a stage called senescence, when they no longer function efficiently and begin causing residual damage to neighboring cells and tissues. Elevated levels of senescence markers have been found in postmortem brain tissue of people with PD, suggesting that accelerated brain aging may be associated with PD. Previous research conducted by Dr. De Miranda and her lab at the University of Alabama at Birmingham has shown that environmental toxicants (such as pesticides, organic solvents and heavy metals): 1) are correlated with an increased risk of PD, and 2) trigger increased levels of the senescence marker p16 in glial cells near degenerating dopaminergic neurons.

To further unravel how environmental toxicants impact cell senescence in the brain and PD pathology, Dr. De Miranda will first use mice that have been genetically engineered to allow her to visualize and measure p16 expression across the brain. After exposing these mice to environmental toxicants associated with elevated PD risk, she will map which cell types and regions in the brain are most vulnerable to becoming senescent after each exposure.

Next, Dr. De Miranda will see if selectively eliminating senescent neurons has a protective effect on the rest of the brain, slowing or preventing PD-like neurodegeneration from toxicant exposure. She will use mice genetically engineered to have neurons with “self-destruct” switches that trigger when they become senescent and start producing p16. By having senescent neurons clear themselves out automatically, Dr. De Miranda hopes to see if their absence reduces damage to surrounding neurons. If successful, this research could spark new PD therapies centered on senescent cell remediation to combat disease progression.

Unlike the senescent cells, Dr. De Miranda has no plans of slowing down and is energized by her Stanley Fahn Junior Faculty Award: “The research funded by this award will show how our environment influences the rate by which we age, potentially opening new doors for therapeutic treatments or strategies to prevent exposure, aging and PD… I am grateful for the continued support from the Parkinson's Foundation to understand how the environment

influences PD risk, an important but understudied topic in PD research.”

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