May 10, 2023
While still in the developmental stage, genetic and cell-based therapies hold some promise for people with Parkinson’s disease (PD). This webinar will review what those considering gene-based or cell-based therapy may expect in terms of symptom management and disease progression.
Roger Barker, BA, MBBS, MRCP, PhD
University of Cambridge
Researchers have discovered several genes that are associated with the risk of developing Parkinson’s disease (PD). To better understand this relationship, the Parkinson’s Foundation is conducting a large population study, PD GENEration: Mapping the Future of Parkinson’s Disease, a national initiative that offers genetic testing and counseling for Parkinson's-related genes at no cost for people with PD. Since different ethnic groups may have differences in their genetic backgrounds, possibly affecting the course of their disease, PD GENEration is now expanding beyond the borders of the mainland U.S. to Hispanic communities in Puerto Rico and the Dominican Republic.
Our guest in this episode is Rebeca De Leon, Associate Director of the Clinical Research Department at the Parkinson’s Foundation. She explains why it is important to include people of diverse backgrounds in the study, how and where the Foundation is reaching out to enroll people from a range of communities in PD GENEration, and ultimately, how participation in the study will help scientists better understand the disease.
Released: September 19, 2023
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The only way we can find a cure for Parkinson’s disease (PD) is through research. Although 10 million people live with the disease worldwide, research in PD is severely underfunded. The Parkinson’s Foundation is committed to closing the funding gaps in research and increasing access to healthcare and quality-of-life programs. The Reach Further campaign is a four-year fundraising initiative that will raise an additional $30 million to support and accelerate progress on these goals.
On September 19, the Parkinson’s Foundation is hosting A Day to Reach Further, a special day of giving that highlights the tremendous progress we have made thus far. As part of this day, Rune Labs, provider of StrivePD, has generously agreed to match all gifts made on A Day to Reach Further up to $10,000.
On A Day to Reach Further, help us fund these vital research initiatives that move us toward a cure:
To cure Parkinson’s, we need to know exactly what causes it. Our research team finds and funds scientists who focus on unraveling the basic biology of Parkinson’s. This year, we awarded grants to 30 scientists who are devoted to deciphering PD and finding new ways to attack it and stop progression.
Through our grants, we fund high-risk research that typically does not receive federal funding, which means we are advancing ideas that can lead to high rewards. Studies span from untangling the connections between inflammation, aging and Parkinson’s; to connecting environmental exposures and Parkinson’s through accelerated brain aging; and deciphering gait signaling to improve movement therapies. Meet some of our researchers here.
Our research grants, fellowships and partnerships help scientists explore innovative ideas and keep them in the Parkinson’s research field, ensuring that we continue to fund a pipeline of projects that could lead us to a cure.
For a new Parkinson’s drug to go from an idea to an available medication it takes funding. Launching a new drug can take years and cost upwards of one billion dollars. We are accelerating this timeline alongside Parkinson’s UK, through the Parkinson’s Virtual Biotech, which is focused on building a pipeline of new drugs exclusively for Parkinson’s.
The Parkinson’s Virtual Biotech is directly investing in 13 medications that either address symptoms or aim to slow, stop or prevent the disease altogether. Some examples of these projects include:
The Parkinson’s Virtual Biotech ensures that promising Parkinson’s treatments are not lost in the development pipeline due to lack of funding. Through this exciting initiative, we believe we can find the next life-changing treatment in years, not decades.
Genetics research can fast track the discovery of new PD treatments. Right now, pharmaceutical companies are developing early-stage therapies or drugs that target people with specific genetic mutations. These new drugs are being designed to slow or even stop PD. Some studies are already enrolling people in clinical trials. However, it can take years to fill these trials. For just one trial that needs 300 participants with a specific PD genetic mutation, researchers may screen up to 15,000 people.
PD GENEration: Mapping the Future of Parkinson’s Disease accelerates clinical trial recruitment — and their results. Our groundbreaking study offers genetic testing and counseling to people with PD at no cost. So far, more than 10,500 people have enrolled in the study and 12.7% of participants have tested positive for at least one of the seven Parkinson’s-related genes. Seventy-four percent of participants have never participated in a PD research study prior to PD GENEration, opening doors for people to join other research studies and advance the field.
The faster we recruit participants in this study, the sooner clinical trials can begin — and the closer we are to a research breakthrough.
Each year, 90,000 Americans are diagnosed with Parkinson’s disease. By participating in A Day to Reach Further, you are directly investing in research that we believe will lead to new treatments and ultimately, a cure. Make a gift at Parkinson.org/ReachFurtherDay.
2023 Impact Award
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.
Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers.
from the Parkinson's community
2018 Postdoctoral Fellowship
2023 Stanley Fahn Junior Faculty Award
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.”
Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers.
from the Parkinson's community
2023 Stanley Fahn Junior Faculty Award
The progressive nature of Parkinson’s disease (PD) is due in part to the spread of a misfolded protein called alpha-synuclein through the brain. Alpha-synuclein forms clumps that clog up brain cells (i.e., neurons), leading to their eventual degeneration. These clumps can also spread from neuron to neuron and trigger the misfolding of other functional alpha-synuclein in those new destinations. Sunil Kumar, PhD, a recipient of a Parkinson’s Foundation Stanley Fahn Junior Faculty Award, has identified a potential new way to stop this spread through the use of a biomimicry approach. In this approach, they use a class of ligands called “foldamers”, which mimic the chemical and structural fingerprints of the clumping alpha-synuclein and inhibit this toxic process.
In his lab at the University of Denver in Colorado, Dr. Kumar will further investigate and refine the design of his these foldamers. These foldamers are bioengineered compounds that aredesigned to physically wrap around other proteins and inhibit their toxic functions. One of these foldamers has proven itself to be especially good at wrapping around misfolded alpha-synuclein and preventing their spread in petri dish, roundworm and mice models of PD.
Next, Dr. Kumar will inject different doses of the foldamer into mice experiencing PD-like symptoms due to spreading alpha-synuclein clumps to find a minimum dose. He will then look at how the treatment affects neuronal health, motor function and overall survival in these PD-like mice compared to controls. If the foldamer works as intended, the treated mice should show improvement as the foldamer stops misfolded alpha-synuclein spread.
Then, Dr. Kumar will tune the design of this foldamer by altering various key features to see if he can improve the foldamer’s capability to restrain misfolded alpha-synuclein. These variations will be tested in Dr. Kumar’s previously utilized petri dish and roundworm PD models, comparing their effectiveness to the original design. If any work better, he will test them in the mouse model as well.
Dr. Kumar is thrilled at the opportunity to investigate the potential of PD foldamer therapies with the support of this Stanley Fahn Junior Faculty Award: “This award means a lot for an assistant professor who is starting a career in the field of Parkinson’s disease and will give me the opportunity to try new ideas, which will further establish my career in this field.”
Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers.
from the Parkinson's community
2023 Stanley Fahn Junior Faculty Award
For both healthy relationships and brains, communication is key. In the brain, this communication is done by neurons relaying messages from region to region using neurotransmitters such as dopamine. Parkinson’s disease (PD) disrupts these lines of communication, breaking down important messaging neurons and preventing neurotransmitter release.
Levodopa, widely considered the first-line drug for the management of PD symptoms, works by restoring dopamine levels in the brain to keep neuronal communication going. However, this dopamine restoration does not alleviate all symptoms of PD, raising the question of what other neurons and neurotransmitters are involved. Rebekah Evans, PhD, recipient of a Parkinson’s Foundation Stanley Fahn Junior Faculty Award, has devoted her research to answering this question.
Dr. Evans suspects that cholinergic neurons, which communicate using the neurotransmitter acetylcholine as opposed to dopamine, might be linked to balance and gait symptoms of PD that are not relieved by levodopa or other dopamine-based treatments. Specifically, she believes that in PD, cholinergic neurons in the pedunculopontine nucleus (PPN) region of the might break down. This, in turn, forces other PPN neurons to inefficiently pick up the slack, leading to the balance and gait symptoms.
To investigate this hypothesis, Dr. Evans and her team at Georgetown University in Washington, DC will be damaging PPN cholinergic neurons in the brains of mice and seeing how other PPN neurons functionally adapt and change in response. Next, she will measure how these adapted PPN neurons activate during different mouse behaviors such as exploring, running and grooming, comparing their activity to those of control mice without cholinergic neuron damage.
Finally, Dr. Evans will look into whether the adapted PPN neurons change their communication patterns with neighboring brain regions. She expects that these neurons become “overly-talkative” with other cholinergic neurons outside of the PPN but maintain normal communication with PD-associated dopamine neurons, contributing to the dopamine-resistant symptoms observed.
With the support of this award, Dr. Evans is excited to start uncovering the mysteries and impacts of cholinergic neuron loss in PD: “Understanding these downstream effects will lay a foundation for developing focused treatments and interventions to prevent pathological circuit alterations in the early, pre-dopaminergic-degeneration stages of Parkinson’s disease… I am so excited to be able to continue this line of research and to fully invest in it to push it forward quickly and rigorously.”
Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers.
from the Parkinson's community
2023 Launch Award
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.
from the Parkinson's community
Understanding how genetics play a role in Parkinson’s disease (PD) is a crucial step to uncovering improved treatments and a cure for PD. Niccolo Mencacci, MD, PhD, has dedicated his career to identifying novel disease-associated genes responsible for Parkinson’s disease, dystonia and other movement disorders, and working with patients who have familial or suspected genetic movement disorders.
“When we identify genetic causes of neurodegeneration, we know that those genes are critical in disease mechanisms. So, it doesn’t matter how frequent or rare it is, if a gene is linked to a condition, it means we need to study how it works in the neurons,” he said. “This could pave the way for new understanding of the disease mechanism, potentially leading to new therapeutic approaches.”
Dr. Mencacci is an Assistant Professor of Neurology at Northwestern University, where he runs the movement disorders genetics clinic. The creation of the clinic came from his interest in better understanding the genetics of movement disorders, and it is a multidisciplinary space that includes in-depth neurological assessment and state-of-the-art genetic tools and is run in partnership with a genetic counselor. This combination allows him to study patients and families with Parkinson’s disease and other movement disorders and determine a molecular diagnosis for their condition.
“This is truly the basis for what we call precision medicine, or precision neurology,” he said. “This is a new type of program that not many other centers have, so we are trying to build it ourselves. My expertise is as a movement disorders neurologist, but I also have a PhD in human genetics, so that’s why we decided to shape the clinic this way. It’s a clinic at the border between clinical practice and research, and there’s a lot of back and forth between the two fields.”
Dr. Mencacci is also the co-lead for the Monogenic Hub of the Global Parkinson’s Genetics Program (GP2), a five-year program aimed at identifying new monogenetic causes of Parkinson’s disease around the world. While previous genetic studies have mostly focused on people of white European descent, one of the major goals of the GP2 study is go beyond this group and study more people from historically marginalized populations around the world.
Separately, he is researching the genetic and molecular mechanisms of PD. He was awarded the Parkinson’s Foundation 2021 PD GENEration Fellowship Award for this work. The award allowed him to take this work, which began during his fellowship, into the next stage of his career, protecting some of his clinical time to focus on this important research.
“An exciting part of what I do in the lab in trying to understand how certain genetic mutations linked to rare forms of Parkinson’s disease may affect biological pathways that are important for disease mechanism,” he said. “This research can be hard to continue because it takes a lot of time. The support I received from the Parkinson’s Foundation was instrumental in protecting my role in this research and gave me the enthusiasm to continue this work. It’s very important to support young researchers and their research interests.”
Dr. Mencacci looks forward to the potential his research can have to improve the health and lives of people with PD. His work with people who have genetic links to PD keeps his motivation high.
“On a daily basis, I think about what an exciting time it is for genetics,” he said. “We are finally seeing the first clinical trials for patients who have genetic forms of Parkinson’s disease. For many years, we have been identifying genetic forms of Parkinson’s, but it made little difference in clinical practice. Now, we’re learning more about how genetics can influence how we manage treatment for a patient.”
He is also grateful for the support of the Parkinson’s Foundation and its backing of genetics research in Parkinson’s disease.
“The support the Parkinson’s Foundation offers people with Parkinson’s to help them understand the disease is incredible, but what they are doing to support the research community is also so important,” he said. “I’m grateful for their support of my research and for their incredible PD GENEration study, which is forming the way that genetics can be applied to Parkinson’s disease and makes genetic testing so accessible for people with Parkinson’s. It’s really changing the culture in the field of Parkinson’s disease.”
For more information on our genetics initiative, PD GENEration: Mapping the Future of Parkinson’s Disease, visit Parkinson.org/PDGENEration.
Considered “atypical Parkinsonian syndromes,” over half of people with progressive supranuclear palsy (PSP), corticobasal degeneration (CBD)/corticobasal syndrome (CBS), and multiple system atrophy (MSA) are initially misdiagnosed with Parkinson’s disease (PD) due to similarities in early symptoms as well as lack of awareness of these rare, neurodegenerative diseases among many healthcare professionals and the general public.
This is the first of three podcast episodes within our atypical parkinsonism podcast series, organized in partnership with CurePSP and designed to address the overview, treatment and care of PSP, CBD and MSA.
In this first episode of the series, Dr. Alex Pantelyat, Associate Professor of Neurology at Johns Hopkins University School of Medicine shares an overview of atypical parkinsonism, overlaps and differences with Parkinson's disease, the red flags and how PSP, CBD and MSA are diagnosed.
Dr. Pantelyat has disclosed that he is a Scientific Advisory Board Consultant for MedRhythms, Inc. and a consultant for both Ferrer Internacional, S.A. and SciNeuro Pharmaceuticals.
Podcast host, Dan Keller, has disclosed that he has no relevant financial disclosures.
Released: September 5, 2023
Don't forget to subscribe! There are many ways to listen: Apple Podcasts, TuneIn (Amazon Echo), Spotify or RSS Feed. (Need help subscribing? See our quick guide.)
For all of our Substantial Matters podcast episodes, visit Parkinson.org/Podcast.
