2023 Launch Award  

Discovering the Hidden Healthy Role of a Parkinson's-associated Protein

Proteins are molecules that play critical roles in the body. Chemical modifications can be made to proteins to subtly or dramatically change their form and function. Alpha-synuclein, a protein found in neurons (i.e., brain cells), has a particular modification called Ser129P that has been linked to Parkinson’s disease (PD). However, the intended function of this modification in healthy neurons is not currently known. Leonardo Parra-Rivas, PhD, recipient of a Parkinson’s Foundation Launch Award, seeks to identify the role of Ser129P alpha-synuclein to better understand how it may go awry in the context of PD.

All alpha-synuclein proteins found in Lewy bodies — protein clumps formed by misfolded alpha-synuclein that have been associated with neuronal degeneration — have the Ser129P modification, making it a hallmark of PD. Despite this, recent studies have shown that neurons need at least a small amount (~4%) of their alpha-synuclein to have this modification to work properly, raising questions as to the functional importance of Ser129P alpha-synuclein in healthy cells.

Dr. Parra-Rivas, a Postdoctoral Research Fellow in the lab of Dr. Subhojit Roy at the University of California San Diego, hopes to answer these questions. He will first determine if Ser129P is required for alpha-synuclein to function properly. Using genetically modified neurons (both from mice and humans) grown in petri dishes, Dr. Parra-Rivas will compare the activity of alpha-synuclein with and without Ser129P, looking at the protein’s ability to regulate neurotransmitter release.

Next, Dr. Parra-Rivas will investigate whether Ser129P mediates the contact between alpha-synuclein with two partner proteins, VAMP2 and synapsin. Using similar neuron models as before, Dr. Parra will conduct studies to measure how much normal alpha-synuclein binds to those partner proteins in the presence and absence of Ser129P.

Finally, Dr. Parra-Rivas will test the hypothesis that Ser129P can suppress alpha-synuclein toxicity, and that Lewy bodies are not toxic themselves, but rather a protective mechanism. He will create neurons with PD-like dysfunction and see how the presence or absence of Ser129P affects the formation of Lewy bodies and the overall health of the neuron. If the neurons without Ser129P do not form Lewy bodies and fare worse, that will provide encouraging evidence on the health importance of Ser129P and guide the way for potential PD therapies that take advantage of the modified protein.

For Dr. Parra-Rivas, receiving this Launch Award to support his research is motivating professionally and personally: “Receiving this award is an honor and a big responsibility for me. PD affected my grandfather for several years before passing; this personal experience inspired my scientific commitment to elucidating this disease. My research aims to establish a new paradigm defining the physiological role of alpha-synuclein Ser129P at synapses, offering a new conceptual platform for investigating the function of alpha-synuclein in PD with implications for drug development and gene therapy.”

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

I have been a huge Neil Diamond fan all my life, and I was upset when I heard the news that Neil would no longer be touring due to his fight against Parkinson's disease (PD). Parkinson’s has affected many people in my personal life; my late grandfather and my wife’s late grandfather both lived with PD, and several others close to us are battling the disease today.

One day, my brother-in-law asked me how much Neil Diamond music I had in my collection. I dragged all my tunes onto a playlist, and it came out to over 400 different songs and 24 hours of his work! "I am", I said, "a believer that 24 hours of Neil would be a perfect day." After thinking about this idea for a few years, we made the decision to hold a "Neil-a-thon" to raise money for the Parkinson's Foundation.

With a bunch of help from my family members, we held the first Neil-a-thon on July 29, 2023. The event started at 3 a.m. and we continuously played Mr. Diamond's songs until 3 a.m. the following day. To pass the time, we developed a menu that included a different little drink and snack for each of the 24 hours. The menu included items like "Song Sung Blueberry Muffins," "Holly Holy Guacamole," "Cherry, Cherry Cheesecake" and "Sweet (and Sour) Caroline Chicken."

Throughout the course of the day, friends and family dropped in, had fun, sang along and donated funds to the cause. Overall, we raised over $2,800 for the Parkinson's Foundation. We had so much fun that we aim to make this an annual event.

We hope that the funds can be used to support the fight against PD and help people with Parkinson’s live better lives. If our efforts could be used to support someone in need, we would all be able to say that we feel..."so good, so good, so good!"

Have a creative idea for a fundraiser? Become a Parkinson’s Champion today.

2023 Postdoctoral Fellowship 

Developing Cutting-Edge Tools to Control and Study Dopamine Signaling

The biological hallmark of Parkinson’s disease (PD) is the progressive loss of dopamine neurons in the brain. In healthy neurons, the neurotransmitter dopamine and its receptors are carefully regulated and transported to facilitate motor function. Many PD-related mutations affect this regulation, but it has been difficult for researchers to fully investigate these complex processes without more sophisticated methods. Chelsie Kadgien, PhD, recipient of a Parkinson’s Foundation Postdoctoral Fellowship for Basic Scientists, has developed and will be testing novel research tools that will allow her to not just study dopamine signaling in greater detail, but to manipulate it and track the effects in real time as well.

Working with her mentors Dr. Matthew J. Kennedy and Dr. Christopher P. Ford at the University of Colorado Anschutz Medical Campus, Dr. Kadgien has created two different methods to control and investigate dopamine signaling in mouse brains. The first method involves reprogramming neurons to produce small proteins called “nanobodies” that bind to dopamine receptors. These nanobodies stick to dopamine receptors right after they are formed inside the cell and prevent them from being shuttled to the cell surface where they are needed, leading to a reduction in dopamine reception — similar to what is caused by certain PD mutations.

Dr. Kadgien can also release the nanobodies from the inside of the cell chemically, allowing her to control when dopamine reception is turned back on and by how much. This will provide insight into how therapies that restore dopamine receptor levels could be used for people with PD.

The second tool that will be tested involves optogenetics, the use of genetically engineered compounds that can be triggered by light. Dr. Kadgien has designed a light-controlled neurotoxin that prevents the release of dopamine from brain cells, mimicking how PD mutations can prevent dopamine signaling. Not only is this neurotoxin activated by light, but it is also reversible. When left in the dark for eight hours, the toxin’s effects wear off and dopamine release is restored. This powerful tool will allow Dr. Kadgien to study dopamine signaling impairments and restoration in a wide range of ways that have never been possible before.

By testing and refining both dopamine pathway manipulation methods, Dr. Kadgien will lead the way for future research into PD therapies that can best restore dopamine signaling and improve the lives of people living with PD. Speaking on what this award means to her, Dr. Kadgien said “I am incredibly honored to be selected for this award amongst many talented peers … [This research] will build the foundation for my career studying how disruptions in communication between brain cells can lead to Parkinson's disease. I hope my work will lead to improvements in quality of life for people living with the disease and their families.”

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

2023 Postdoctoral Fellowship 

Developing a Drug Screening Platform to Identify Inhibitors for Different Alpha-synuclein Strains

While every person with Parkinson’s disease (PD) experiences unique symptoms and progression, all people with PD have a protein in their brain called alpha-synuclein that is not working like it should. Recent studies have shown that each person with PD may have a unique misfolded version of this protein, which may be related to disease severity.

Currently, there is no treatment for PD targeting alpha-synuclein strains, but Kundlik Gadhave, PhD, recipient of a Parkinson’s Foundation Postdoctoral Fellowship for Basic Scientists, is hoping to change that with his upcoming research.

From his lab at Johns Hopkins University in Baltimore, MD, Dr. Gadhave’s research is dedicated to developing an alpha-synuclein strain screening assay that will help to identify inhibitors for different variants, or strains, of misfolded alpha-synuclein.

With the help of his mentor Xiaobo Mao, PhD, Dr. Gadhave has already identified key inhibitors. Dr. Gadhave will use these inhibitors for screening alpha-synuclein proteins from spinal fluid samples of people with PD.

What are Lewy bodies? Lewy bodies are toxic aggregations, or clumps, of alpha synuclein that affect chemicals in the brain, leading to problems with thinking, movement, behavior and mood.

The identified compounds that bind to misfolded alpha-synuclein may also be able to inhibit the formation of Lewy bodies, which are strongly linked to PD. The second half of Dr. Gadhave’s research will test whether the compounds found to bind specific alpha-synuclein strains can slow PD from advancing. This research could lead to the generation of personalized PD therapies that use inhibitors capable of counteracting a unique alpha-synuclein strain.

Dr. Gadhave believes this research can improve how we treat Parkinson’s. “Completing this research will lead to the development of a new compounds for alpha-synuclein strains, which will benefit the therapeutic development for PD.”

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

2023 Postdoctoral Fellowship 

Deciphering gait signaling to improve movement therapies

The metaphor of “a walk in the park” implies that something is simple and easy; however, the neuroscience involved in such an activity is incredibly complex and relatively unstudied. This complexity is most evident in the context of movement disorders such as Parkinson’s disease (PD), where current therapies struggle to address the movement issues associated with the condition. Rodrigo Manuel Paz, PhD, recipient of a Parkinson’s Foundation Postdoctoral Fellowship for Basic Scientists, has homed in on a specific region of the brain crucial for walking and will be devoting his research to better understanding how it works and how novel therapies can better treat trouble moving or walking in people with PD.

Dr. Paz is particularly interested in the brain’s way of managing gait, the repeating pattern of coordinated muscle activity associated with walking. In PD, gait impairment leads to loss of balance and risk of falling, as the brain struggles to maintain a consistent walking rhythm.

Working alongside his mentor, Dr. Alexandra Nelson at University of California San Francisco, Dr. Paz plans to investigate how gait may be regulated by the motor thalamus region of the brain. The motor thalamus receives signals from the basal ganglia, a neuron hub which contains the dopamine neurons that are lost in PD, and relays those signals to the motor cortex, which ultimately communicates the movement command to the muscles.

Dr. Paz will use mice in his experiments, comparing those with PD-like neurodegeneration to those without such neuron loss. A device will be attached to the mice that allows Dr. Paz to measure the activation of motor thalamus neurons as the mice walk freely, while high-speed cameras capture and correlate those activations to their gait. These data will provide insight into how the motor thalamus neuron activity may connect to walking coordination and whether such activity is impaired in PD-like mice, contributing to movement dysfunction.

Next, Dr. Paz will use brain slices from mice with and without PD-like neurodegeneration to better understand the mechanistic changes that may be occurring between the motor thalamus and its associated brain regions. Using optogenetics — a technique by which light can be used to trigger genetically-altered cells — he will stimulate neurons from the basal ganglia and motor cortex to watch and calculate motor thalamus responses and determine how neurodegeneration affects that important communication pathway in the brain.

Dr. Paz is enthusiastic about what such results may mean for future therapies. “By understanding how motor thalamus influences gait and how changes in synaptic inputs drive impaired gait signals in motor thalamus, this project will establish a fundamental framework for improving therapies specifically aimed at alleviating gait deficits in people with PD,” he said.

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

2023 Postdoctoral Fellowship 

Uncovering how an alternative mitochondria cleanup process may reduce brain inflammation

Inflammation is the body’s way of dealing with unwanted invaders, mobilizing immune cells to contain, destroy, and clean up areas of infection or injury. However, this process sometimes malfunctions, leading to cell and tissue damage. There is evidence to suggest that such inflammation misfires occur in Parkinson’s disease (PD) and may be contributing to neuron degeneration; however, the source of these potential inflammatory errors has not yet been identified. Tahnee Saunders, PhD, recipient of a Parkinson’s Foundation Postdoctoral Fellowship for Basic Scientists, believes that answer may lie in mitochondria, the powerhouses of the cell.

Mitochondria are organelles, or “mini organs,” found in nearly all cells that use oxygen to power numerous critical biological processes. Like any other hard-working engines, mitochondria eventually get worn out and may break down, requiring disposal by the cell in a process called mitophagy (from the Latin “phagus”, meaning “to eat”) that involves the proteins PINK1 and Parkin. In some cases of young-onset PD, those two mitophagy proteins are dysfunctional, preventing the disposal of broken mitochondria and potentially contributing to increased inflammation and neurodegeneration.

Dr. Saunders, working with her colleagues in the lab of Associate Professor Michael Lazarou at the Walter and Eliza Hall Institute in Victoria, Australia, will be investigating a new form of mitophagy that may hold therapeutic promise for those with PD involving mitochondrial damage. This form of mitophagy occurs when the inner mitochondrial membrane (IMM) becomes exposed and is used to start the disposal chain reaction independent of PINK1 and Parkin. Using cells from both PD-model mice and from people with PD, Dr. Saunders will define the key factors driving IMM-induced mitophagy while also exploring the prevalence of this pathway in different cell types found in the brain.

With the knowledge gained from this research, novel therapies may be developed that boost IMM-induced mitophagy in the brains of those with PD, including individuals with PINK1 or Parkin deficiencies, potentially reducing inflammation and consequent neuron loss. Such therapies could one day be life-changing to those with PD, slowing or even stopping the progression of the disease.

When asked what this Parkinson’s Foundation grant award means to her, Dr. Saunders said it “has been a huge validation of the work I am doing and has given me a clear vision for my future research into Parkinson’s disease…I feel extremely passionate about helping those living with Parkinson’s.”

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