Investigating How the Puzzling G2385RLRRK2 Mutation Leads to Parkinson’s
While aging and environmental factors are the greatest contributors to developing Parkinson’s disease (PD), Parkinson’s Foundation researchhasfound that approximately 13% of people with Parkinson’s have a known genetic link to the disease. For those people, a small change in their DNA (a DNA variant) contributes to PD-associated cellular disruptions.
Variants of the gene that create a protein called Leucine-Rich Repeat Kinase 2 (LRRK2) are found in 1-5% of all PD cases. Significant progress is being made to understand how LRRK2 variants lead to PD, but some variants are more complicated than others, leaving gaps in our scientific understanding.
Patrick Lewis, PhD, recipient of a Parkinson’s Foundation Trailblazer Award, is devoting his research to one perplexing LRRK2 variant called G2385R. This variant affects a different area of the LRRK2 protein than other more well-studied variants. Interestingly, the effects of the G2385R variant on cell function may be the opposite of other LRRK2 variants, raising questions about how it leads to PD.
Decoding Gene Variant Naming
Scientists use a specific alphanumeric pattern to name genetic variants, which commonly goes letter-number-letter. The first letter and number refer to an amino acid — building blocks of proteins — at a specific position in a protein blueprint chain. The second letter refers to what the variant changes the original amino acid into, potentially affecting the function of the protein. For G2385R variants, the uncharged glycine (G) in the 2385th amino acid slot in the chain to build LRRK2 becomes a charged arginine (R) instead.
From his lab at the Royal Veterinary College in London, UK, Dr. Lewis is preparing a wide range of experiments to fully understand how G2385R LRRK2 operates within cells and how it contributes to PD. First, he and his team will observe the biochemical activity of the variant protein, comparing and contrasting its functionality to both original LRRK2and otherLRRK2 variants.
They will then monitor how the variant LRRK2 reacts to biological stress within the cell, where it moves and accumulates and how that disrupts other pathways and processes. Finally, Dr. Lewis will test how various drugs, including LRRK2 inhibitors currently undergoing clinical trials, impact G2385R LRRK2, providing insight into potentially useful therapeutics in the future.
The G2385R LRRK2 variant is more common in east Asia than in Europe or America, affecting nearly 2% of people with PD across countries including China, Japan and Korea. Understanding the disease association of this variant will go a long way in advancing treatments not just for those hundreds of thousands of people with the G2385R variant, but for all those with LRRK2 variants as our scientific understanding of the whole protein increases.
When asked about what this support means to him and his work, Dr. Lewis said, “Receiving a Trailblazer Award from the Parkinson's Foundation is really an honor. This project will allow me to develop a new avenue of research investigating LRRK2 to understand how one of the most common Parkinson's risk variants worldwide can increase the likelihood of developing Parkinson's at a functional level.”
Scanning Family Trees for Hidden Parkinson’s Risk Factors
It is widely understood that Parkinson’s disease (PD) is caused by a combination of environmental and genetic risk factors, with unique combinations of these factors for each person. Parkinson’s Foundation researchhasfound that approximately 13% of people with Parkinson’s disease have a genetic link to the disease through one of the seven most common disease-related variants.
The genetic testing from this research has helped connect those people to therapies and research studies directly related to their PD genetic background. However, the large amount of people with PD that do not have those genetic variants implies that there could be more rare disease-associated variants to be discovered.
Paolo Moretti, MD, recipient of a Parkinson’s Foundation Trailblazer Award, is analyzing the genetic family histories of thousands of people with PD to find these previously hidden disease-associated genetic risk factors. By leveraging the power of a unique, rare set of generational genetic data, he hopes to identify new variants to screen for and use to better determine PD risk in families.
“The most important outcome of our studies will be the identification of PD risk variants that are, at least in part, different from those that have been discovered to date.” - Dr. Moretti
Based at the University of Utah in Salt Lake City, a Parkinson’s Foundation Center of Excellence, Dr. Moretti will utilize the vast genealogical and genetic data within the Utah Population Data Base and University of Utah Health Science Center electronic data warehouse. This resource includes highly detailed, multigenerational medical records and DNA samples from families that often date back to the mid 1800s. Using statistical analysis tools, Dr. Moretti and his team will screen for extended families with above-average incidence of PD without common genetic risk factors.
These analyses could uncover more subtle genetic risk factors for PD that could only be spotted by looking at well-documented family tree genetics. Dr. Moretti will then validate these new potential genetic risk factors by scanning for them among larger PD databases, seeing if they are indeed associated with higher risk of disease. Altogether, this research hopes to yield new genetic insights into PD that are crucial to our overall understanding of the disease.
“Receiving the Trailblazer Award is the culmination of an effort that my collaborators and I began a few years ago,” said Dr. Moretti. “With this award, we are hoping to further our understanding of the genetic architecture of PD and to collaborate with other investigators in the field to facilitate genetic and pathogenesis studies in PD.”
This article highlights the ways the Parkinson’s Foundation helped people living with Parkinson’s and the Parkinson’s community in 2025. It highlights:
How we advanced research through funding grants and evolving our genetics study.
Funded local community programs.
Launched new policy effort to improve care and research through advocacy.
Spread Parkinson’s awareness through programs, campaigns and resources.
2025 was a remarkable year for the Parkinson’s Foundation. Over the course of 365 days, we advanced Parkinson’s disease (PD) research while working hard to represent the one million people in the U.S. living with this neurodegenerative disease. We strengthened our connections among care partners and everyone serving the PD community.
With your support, we launched new initiatives and vital PD resources, stayed fast in our commitment to improving PD care and research, and empowering the community through education and new resources.
Thanks to YOU, here are the top 12 ways we made a difference this year:
In a year when federal funding for disease research sharply declined, we significantly increased our investment in Parkinson’s research. We awarded more than $4.3 million across 44 grants. We are proud to fund scientists pursuing innovative studies across diverse areas of PD — driving the development of new therapies, treatments and ultimately a cure for the 10 million people worldwide living with this neurological disease.
Dr. Kim is leveraging AI (artificial intelligence) to advance genetics research. His research seeks to understand how overlapping PD mutations may influence the risk of developing PD.
Providing genetic testing and counseling to 30,000+ people with Parkinson’s, at no cost.
Finding that approximately 12-13% of participants carry a genetic link to PD.
Expanded study to a total of 77 testing sites worldwide and counting — adding sites in Mexico, Colombia, Chile, Peru and El Salvador.
We also launched an exciting new pilot program, PD Trial Navigator, to help advance PD GENEration’s goal of accelerating genetic-focused clinical trials. This program helps inform PD GENEration participants about Parkinson’s genetic trials they may qualify for based on their genetic results.
Hosting a national roundtable on Parkinson’s care and innovation to identify national priorities to improve care for people with PD.
Co-hosted the 2025 Parkinson's Policy Forum, where 250 people with PD, family members and advocates from 45 states gathered in Washington, D.C. to urge Congress to accelerate progress toward better treatments and a cure.
We awarded more than $1 million in community grants for programs that help people living with PD across 38 states. Our 2025 grants fund local programs that provide exercise and educational support for people with PD and their care partners and address mental health needs. Since 2011, the Foundation has devoted more than $12.7 million in community-based programs, reaching a combined 81,000 people with PD and care partners.
Pictured: Parkinson’s Foundation Community Grantee, Parkinson's Exercise Program For You, in Dana Point, CA, offers PD-tailored exercise programs.
To find your nearest exercise or wellness class, visit your local chapter’s webpage or call our Helpline at 1-800-4PD-INFO (1-800-473-4636).
5. Appointed our first-ever Chief Medical Officer.
This year, we welcomed Sneha Mantri, MD, MS, as Chief Medical Officer of the Parkinson’s Foundation. A nationally recognized movement disorders specialist and educator, Dr. Mantri believes in getting to know her patients and personalizing their treatments. “I'm excited to bring that philosophy of care to this role and address the needs of people with Parkinson’s on a national scale,” she said.
Look out for virtual events featuring Dr. Mantri in 2026.
6. Moved two Parkinson’s Virtual Biotech drugs into trials.
Parkinson’s Virtual Biotech is a research-driven investment fund we support alongside Parkinson’s UK. In 2025 we shared two exciting advances:
Project ASPro-PD became the first Parkinson’s Virtual Biotech project to enter a large phase 3 trial, assessing whether ambroxol (a common cough medicine ingredient) can slow the progression of Parkinson’s. This trial is the closest to delivering a new treatment.
A new drug from NRG Therapeutics, designed to repair the mitochondria that power brain cells, is advancing to clinical trials for Parkinson’s and ALS (amyotrophic lateral sclerosis). This progress was made possible through early investment from the Parkinson’s Virtual Biotech, proving how our venture philanthropy model fuels innovation — turning bold ideas into real possibilities for people living with Parkinson’s and making investments less risky for future funders.
We know that healthcare appointments for Parkinson’s can feel overwhelming. Which is why we published new content and tips dedicated to help people with PD and care partners advocate for their best care. Use our Steps to Prepare for a Parkinson’s Appointment worksheet for a step-by-step guide to choosing your top three appointment topics.
8. Raised $263,000 on Parkinson’s Foundation Day of Giving.
Our incredible community came together and made our third annual Day of Giving the most successful so far, raising double the amount raised in 2024. Our steadfast supporters made this special day a success, raising awareness and funds to support our mission to make life better for people with Parkinson’s disease.
9. Facilitated 3,949 community service hours through Parkinson’s Ambassadors.
Volunteers are essential to our mission and help us localize our reach. This year, we trained 239 new Parkinson’s Foundation Ambassadors and brought all our volunteers together at our national Volunteer Leadership Summit.
Etana Soloman joined our People with Parkinson’s Advisory Council to add her voice and help represent young caregivers and people like her mother who are in the later stages of PD. “Being able to care for my mom is truly an honor” Read her story.
10. Reached 8.6 million visits to Parkinson.org and expanded Spanish-language engagement.
Parkinson.org reached a record of 8.6 million visits, including 1.3 million visits to our Spanish content. Every page visit represents an opportunity to connect people with life-changing resources, digital events and actionable ways to help make life better for people with Parkinson’s.
11. 20,000 participants raised more than $8.3 million through community fundraising events.
Parkinson’s Foundation community fundraisers raised an impressive $8.3 million to advance PD research, access to care and life-changing resources in 2025. Together, every person who participates in Moving Day, A Walk for Parkinson’s, Parkinson’s Champion and Parkinson’s Revolution bring us closer to a cure.
Two years after his diagnosis, Brooke Ramsey found Moving Day Columbus. For the last 14 years his family has raised more than $117,000 to help make life better for people with Parkinson’s. Read his story.
12. Engaged with our audience through two awareness campaigns.
In April, we introduced the world to PAM, your guide to Parkinson’s Awareness Month. To raise PD awareness, PAM shared essential information, tips and resources about PD on our social media channels and website.
In April we:
Posted 5 new videos highlighting PD facts everyone should know.
Reached 2+ million visits to Parkinson.org — our most page views in a single month!
Earned 914,000 impressions across our social media posts
In November, for National Family Caregivers Month, we amplified the diverse experiences of caregiving through our Real Care. Anywhere. campaign. We provided tailored resources for three types of caregivers including those caring for someone living with Parkinson’s, those providing care from a distance and those managing PD alone.
Breathing Danger: Study Links Air Pollution to Lewy Body Dementia Risk
🧠 What will you learn in this article?
This article highlights a new study that found that living in an area with higher air pollution was linked to hospitalization for Lewy body dementia (LBD). It discusses:
How 75-80% of people with Parkinson's eventually develop LBD.
Possible causes behind the findings
What this study means for people with PD today.
For years, researchers have suspected that the air we breathe might affect our brain health. Now, a study examining 56.5 million Americans reveals a troubling connection between living in a place with higher air pollution and Lewy body dementia (LBD) — a finding with significant implications for the Parkinson's disease (PD) community, as 75-80% of people with Parkinson's eventually develop LBD.
Lewy body dementia is an umbrella term for two related conditions: dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Both involve the accumulation of abnormal protein deposits called Lewy bodies — which contain clumps of alpha-synuclein protein — throughout the brain. While people with Parkinson's initially experience movement symptoms like tremor and rigidity due to Lewy bodies primarily in neurons within movement-control brain regions, most will eventually develop cognitive symptoms as these protein deposits spread to areas controlling memory and thinking.
The study, which was supported by the Parkinson’s Foundation and led by 2019 Stanley Fahn Jr. Faculty Award recipient Xiaobo Mao, analyzed health records of 56.5 million Americans who used Medicare from 2000 to 2014, across 34,824 zip codes. Researchers matched the zip codes to exposure to PM2.5, tiny particles in the air that come from sources like vehicle exhaust, industrial emissions and wildfire smoke. These particles are so small they can penetrate deep into the lungs and the bloodstream. While PM2.5 is recognized as a health concern and risk factor for dementia, this is the first study to find a link between PM2.5 and Lewy body dementia.
Study Results
The analysis showed that there was a strong link between long-term PM2.5 exposure and higher risk for someone’s first hospital admission for LBD, indicating that living in a place with more air pollution is associated with a greater risk for LBD.
To understand how air pollution could be connected to LBD, the researchers conducted experiments with mice. They found that long-term PM2.5 exposure caused brain shrinkage and cognitive deficits in normal mice, lending support to their initial findings. Interestingly, this effect disappeared in genetically engineered mice lacking alpha-synuclein—the protein that forms the characteristic Lewy bodies. This suggests that alpha-synuclein plays a crucial role in how air pollution damages our brains.
Perhaps most striking, the research team discovered that PM2.5 exposure in mice engineered to display Parkinson's-like symptoms led to the development of what they call “PM-PFF”—a particularly harmful version of alpha-synuclein that is highly resistant to breakdown and especially toxic to brain cells. The team showed that this corrupted protein closely resembles the abnormal alpha-synuclein found in actual LBD patients.
When the researchers exposed mice engineered to develop Parkinson's-like symptoms to air pollution samples from China, the U.S. and Europe for two months, they all consistently produced dangerous “PM-PFF” protein formations, suggesting air pollution is a global concern to brain health.
The team also compared gene expression activity patterns between PM2.5-exposed normal mice and human LBD patients, finding prominent similarities. This pattern match strengthens the evidence that air pollution isn't just correlated with dementia—it may actually cause the biological changes seen in the disease.
Highlights
The study analyzed health records of 56.5 million Americans who used Medicare in a 14-year period, residing in 34,824 zip codes.
Living in an area with higher air pollution (higher long-term levels of PM2.5 particles) was linked to hospitalization for Lewy body dementia (LBD).
In normal mice, long-term PM2.5 exposure caused brain shrinkage and cognitive deficits. These issues depended on the presence of alpha-synuclein, a protein associated with PD and LBD.
In mice engineered to develop Parkinson's-like symptoms, PM2.5 exposure created what they call “PM-PFF”—a particularly harmful version of alpha-synuclein that's highly resistant to breakdown and especially toxic to brain cells.
Gene activity patterns in PM2.5-exposed normal mice were similar to those in human LBD patients.
What Does This Mean?
This research provides the first clear biological explanation for how air pollution might trigger or accelerate the development of Lewy body dementia. The identification of PM2.5 as a specific risk factor means we now have a measurable, modifiable environmental target for disease prevention.
This study, and others like it, have found a clear association between environmental toxicants and neurodegenerative diseases – which is important as this knowledge could inform and impact environmental policies.
This study highlights the importance of reducing exposure to air pollution when possible and continuing proactive steps that support brain health, like regular exercise, quality sleep and staying proactive with medical care.
What do these findings mean to the people with PD right now?
While this research doesn’t change day-to-day treatment for people with PD right now, it strengthens what many in the Parkinson’s community have long suspected — that environmental factors play a real role in disease development and progression. Knowing that air pollution may contribute to Lewy body disease gives us a new area to monitor and advocates another reason to push for cleaner air and stronger environmental standards.
If you are concerned about exposure to air pollution, or PM2.5 particles, talk to your doctor.
Learn More
The Parkinson’s Foundation believes in empowering the Parkinson’s community through education. Learn more about PD and the topics in this article through our below resources, or by calling our free Helpline at 1-800-4PD-INFO (1-800-473-4636) for answers to your Parkinson’s questions.
Small particles in the air with a diameter of 2.5 micrometers or less that come from sources like vehicle exhaust, industrial emissions, and wildfire smoke.
Meet a Researcher Working to Make Adaptive DBS More Effective
🧠 What will you learn in this article?
This article highlights ongoing research aimed at improving the effectiveness of adaptive deep brain stimulation. It discusses:
The definition of adaptive DBS (aDBS).
Adaptive deep brain stimulation and how it can alleviate Parkinson’s symptoms.
Research into whether “entrained-gamma” signals may make adaptive deep brain stimulation more effective than the “beta” signals currently used in the treatment.
How this research could improve the lives of people with Parkinson’s.
Over time, Parkinson’s disease (PD) medications can begin to lose their effectiveness. When this happens, deep brain stimulation (DBS) can be a promising treatment option for certain candidates. For DBS, electrodes are implanted into the brain that deliver controlled electrical stimulation that counteracts PD symptoms.
Most DBS systems are designed to deliver consistent stimulation based on settings set and updated by physicians. However, a newer version called adaptive DBS (aDBS), recently approved by the U.S. Food and Drug Administration (FDA) for clinical use, monitors brain signals associated with PD symptoms in real time and adjusts stimulation automatically. This ability to auto-adjust stimulation has the potential to enhance DBS efficiency and minimize side effects, improving quality of life for those that use it.
Adaptive DBS (aDBS) monitors brain signals associated with Parkinson’s symptoms in real time and automatically adjusts DBS stimulation.
Lauren Hammer, MD, PhD, recipient of a Parkinson’s Foundation Stanley Fahn Junior Faculty Award, is working to make aDBS even more effective by determining which types of brain signals offer the best information on how to adjust stimulation in response to symptoms. Current aDBS technology monitors low-frequency brain waves called “beta” signals, but Dr. Hammer believes that higher frequency “entrained-gamma” signals may be better for predicting and controlling PD symptoms.
“This research aims to advance deep brain stimulation for Parkinson’s disease by identifying the most effective neural signal to guide adaptive DBS,” said Dr. Hammer. “Results could support expanding the set of neural signals used for clinical aDBS, enabling more effective and personalized treatment.”
From her lab at the University of Pennsylvania, a Parkinson’s Foundation Center of Excellence, Dr. Hammer will first run an in-laboratory assessment where people with PD perform various movement tasks while their brain signals are monitored. This will provide data as to which type of signal — beta or entrained-gamma — offers a more accurate reflection for when PD symptoms like involuntary movements are occurring.
Dr. Hammer will then take a small group of people with DBS for PD and upgrade them to aDBS for an at-home study. After participants are programmed for aDBS stimulation using both beta signals and entrained-gamma signals, they will switch weekly between these settings, recording how well their symptoms are controlled at home.
At the end of the trial, Dr. Hammer and her team will have data to suggest which signal type guided the best aDBS experience for different types of people with PD.
“I’m deeply grateful to the Parkinson's Foundation for investing in early-career scientists and accelerating progress toward better care and a cure.” – Dr. Hammer
“Receiving this Parkinson’s Foundation award is an incredible honor and an important milestone in my journey to improve the lives of people with Parkinson’s disease,” said Dr. Hammer. “As a new faculty member starting my own laboratory, this support comes at a critical time — helping me build the foundation for a research program focused on developing next-generation deep brain stimulation therapies. Funding at this early stage is vital to turning promising ideas into impactful treatments, and this award will help bridge the gap between training and long-term research support.”
Combining AI and Skin Biopsies to Detect Parkinson’s Years Earlier
Parkinson’s disease (PD) is primarily diagnosed clinically, meaning that a diagnosis is based on an assessment of symptoms and medical history. While certain tests looking at PD biomarkers can help support a diagnosis, currently there is no specific lab test that can be used to diagnose PD by itself. Additionally, there is currently no way to efficiently predict who may be at risk for developing PD, which is critical for potential therapeutic interventions.
Jay Alberts, PhD, recipient of a Parkinson’s Foundation Trailblazer Award, is leveraging an explainable artificial intelligence (AI) model to identify those at-risk for developing PD within two years based on medical history analysis. He will then invite those deemed “high-risk” to test out a new diagnostic test that could detect PD with a simple skin biopsy, improving our ability to detect the disease earlier.
“This project leverages the power of artificial intelligence to provide greater understanding and use of a promising biomarker test in individuals who may be in the pre-symptomatic phase of PD.” – Dr. Alberts
Alpha-synuclein, a protein whose biochemically altered form is prone to neuron-damaging clumping in PD, is widely agreed to be a strong candidate biomarker for the disease. Recent research has found that biochemically altered alpha-synuclein can readily be detected in skin samples of those with symptomatic PD. Dr. Alberts is working to see if the same is true of those with pre-symptomatic PD and if AI can best identify people who should undergo this testing.
Dr. Alberts and his team at the Cleveland Clinic, a Parkinson’s Foundation Center of Excellence, have developed an AI program that can analyze health records to determine a person’s risk of developing PD within a few years. Importantly, the AI system is “explainable,” meaning that the model can inform patients on the relative contribution of each predicting factor that leads into their overall risk score.
For his study, Dr. Alberts will invite people the AI model has deemed to be high and low risk of future PD to undergo a Syn-One test. This diagnostic test involves three small skin biopsies — each approximately 1/8 of a pencil eraser in size — from which levels of biochemically altered alpha-synuclein are measured. If Dr. Alberts’ hypothesis is correct, then those deemed high-risk for future PD will have higher amounts of this biomarker than those deemed low-risk.
“This project will, for the first time, combine explainable artificial intelligence models developed from the electronic health record to identify and evaluate a scalable approach to screening for Parkinson's disease,” said Dr. Alberts.
If these validation studies go well, this combination of AI-powered risk determination with Syn-One testing could be used to detect PD years earlier than currently possible.
Investigating How Neurons Rebalance Their Roles in Early Parkinson’s
In Parkinson’s disease (PD), cognitive symptoms often appear years before movement symptoms begin. However, these cognitive symptoms — difficulties performing tasks involving decision-making and learning — are linked to many different diseases and therefore difficult to use as an indicator for PD without additional clinical evidence.
Kauê M. Costa, PhD, recipient of a Parkinson’s Foundation Impact Award, is diving into the complex neuroscience of PD to better understand what causes cognitive PD symptoms to occur before movement symptoms. This research could help lead to improved treatments for PD cognitive symptoms and support earlier PD diagnoses.
“This research has the potential to shed light on intrinsic mechanisms of adaptation to cell loss that could be leveraged for developing new treatments for the disease, and to identify early biomarkers of Parkinsonian degeneration, which could be used for early diagnosis and intervention.” – Dr. Costa
As PD progresses, dopamine-producing neurons in the substantia nigra region of the brain lose function and break down. The most fragile of these neurons, and usually the first ones to degenerate, are located in the lateral substantia nigra (lSN) and are important for sending movement signals to another brain region called the dorsolateral striatum (DSL).
Dr. Costa hypothesizes that as these lSN neurons break down in early PD, the neighboring neurons in the medial substantia nigra (mSN) attempt to “pick up the slack”, taking over the lost movement signaling responsibilities. However, doing so means sacrificing efficiency in their other role, which involves cognitive signaling. This could explain why cognitive symptoms appear first, as the brain reorganizes neurons to preserve movement signaling at the expense of cognitive signaling.
From his lab at the University of Alabama at Birmingham, Dr. Costa will test his hypothesis by measuring the abilities of rats to perform learning-based and movement tasks before and after they are induced with simulated PD. Using state-of-the-art brain monitoring technology, Dr. Costa will also record dopamine released by both lSN and mSN neurons over time, observing how they change and adapt as the simulated disease progresses and if they follow his prediction of reorganized signaling roles.
By understanding what is happening in the brain in early PD to cause cognitive symptoms before movement ones, doctors could improve the ability to diagnose the disease earlier, treat cognitive symptoms more efficiently, and potentially delay additional symptoms.
“This Impact Award will allow me to apply my expertise to solving an important question in Parkinson's disease pathology, which I have been thinking about since I was a graduate student,” said Dr. Costa. “I am grateful to the Parkinson's Foundation for the opportunity to pursue my interests in the intersection of basic and translational neuroscience.”
Investigating New Ways to Address Posture Impairment in Parkinson’s
A common symptom of Parkinson’s disease (PD) is impaired posture. Unfortunately, this symptom is resistant to standard dopamine replacement therapies, and not much is known about the neurological mechanisms that lead to it. Left unchecked, posture impairment can lead to serious falls and other injuries for people with PD.
Colum MacKinnon, PhD, recipient of a Parkinson’s Foundation Impact Award, suspects that PD affects brainstem neurons responsible for sending posture-related signals to the muscles of the legs and feet. Investigating this potential mechanism behind PD-related posture impairment may contribute to future treatments that could alleviate this debilitating symptom.
“If successful, this work will be the first to demonstrate that brainstem pathways that control muscle firing properties are altered in people with PD and are associated with postural impairment.” – Dr. MacKinnon
Dr. MacKinnon, with the help of his coinvestigators Dr. Laura McPherson, PT, DPT, PhD, and Dr. Daniel Free, PhD, will enroll people with and without PD, recording and analyzing their posture and gait (walking manner). He will also use a device to measure muscle activity activity as they point and flex their feet, capturing nerve signals important for balance and posture.
From this initial data collection, Dr. MacKinnon expects to see reduced postural muscle activity that is controlled by descending brainstem systems in people with PD, and this reduction will correlate with impaired posture and walking ability.
Next, Dr. MacKinnon will use a noninvasive vagus nerve stimulation device, commonly used to treat migraines and cluster headaches, to stimulate neurons within the brainstem associated with postural control. If his hypothesis is correct, this stimulation will temporarily improve the posture and balance of those with PD as the signals to the ankle muscles are restored. These studies will provide valuable direction for future research and therapeutic development of PD-associated posture impairment, which could significantly improve quality of life for people with PD.
“This award provides the unique opportunity to explore the potential contributions of non-dopaminergic pathways to the abnormal muscle activation patterns observed in people with PD, and to conduct exploratory experiments to test the efficacy of using vagus nerve stimulation to upregulate these pathways, improve muscle activation, gait and postural control,” said Dr. MacKinnon.
Nuria Vendrell-Llopis, PhD, recipient of a Parkinson’s Foundation Impact Award, is uncovering whether the likely biological cause for PD movement symptoms also contributes to PD-linked thinking impairment. Understanding how movement and non-movement symptoms overlap or diverge could lead to new diagnostic and treatment tools for PD cognitive symptoms.
“Our research aims to investigate how the accumulation of alpha-synuclein, a protein associated with Parkinson’s disease, disrupts the brain circuits that support learning and other cognitive functions.” — Dr. Vendrell-Llopis
In PD, clumps of misfolded alpha-synuclein proteins often accumulate in fragile dopamine-producing neurons in the brain. These clumps, called Lewy bodies, disrupt the function of these neurons and contribute to their breakdown over time. These dopamine neurons are important for movement, so movement symptoms caused by their disruption in PD makes biological sense.
However, misfolded alpha-synuclein can also form clumps in other neurons in the brain, including those considered to be important for cognition. To date, the association between Lewy bodies and cognitive PD symptoms is not as well understood. Dr. Vendrell-Llopis, from her lab at the University of Alabama at Birmingham, will utilize cutting-edge brain imaging technologies to observe and measure how alpha-synuclein clumps impact learning patterns in mice. She will inject these clumps into neurons within mice, then train those mice to perform a task that uses these specific neurons to receive a reward.
Some neurons will develop clumps of alpha-synuclein, while others will not. By directly comparing the activity of neurons with and without alpha-synuclein clumps during this learning task, Dr. Vendrell-Llopis hopes to determine if Lewy bodies are a likely cause of PD-related cognitive symptoms.
The data collected from these complex studies will allow Dr. Vendrell-Llopis and her team to see which factors, including alpha-synuclein clumping, aging and neuron loss, most affect cognition. She will also perform longer-term studies with these mice, seeing if their learning abilities diminish over time due to progressive alpha-synuclein impacts.
“The knowledge and tools from this work could make it possible to detect cognitive problems in Parkinson’s disease much earlier, even before standard tests detect any symptoms,” said Dr. Vendrell-Llopis. “Our approach can be used to test new treatments, providing real-time feedback on how therapies impact brain activity and cognitive performance."
Designing Nanobodies that Stabilize Dysfunctional Proteins in Parkinson’s
The most common genetic risk factor associated with Parkinson’s disease (PD) lies in the GBA1 gene. Research from the Parkinson’s Foundation genetics study, PD GENEration, has found the GBA1 gene is present in 5-10% of people with the disease. GBA1 provides the instructions to make a protein called glucocerebrosidase (GCase), which plays an important role in the waste recycling compartment of the cell, known as lysosomes. Variants linked to PD produce unstable or less active versions of GCase. As a result, cells lose part of their cleanup ability, leading to a buildup of harmful proteins such as alpha-synuclein.
Wim Versées, PhD, recipient of a Parkinson’s Foundation Impact Award, has discovered a set of small proteins called “nanobodies” that attach to and stabilize these fragile forms of GCase, restoring their functionality in cells where they are needed most.
Most previous research tried to stabilize GCase using small molecule “chaperones”. These compounds could bind and protect the protein but are often attached to the protein’s active site — the very region needed for its normal function, blocking its activity. The nanobodies, by contrast, stabilize GCase by binding to a previously unexplored site far away from the active site, preserving its natural role.
Think of mutant GCase as a fragile vase you want delivered safely to your home. One way to protect it during shipping is to fill it with solid material. That will prevent it from breaking, but once it arrives you can no longer use it to hold flowers. This is what happens when molecules bind the active site. Nanobodies, instead, act by binding or wrapping on the outside of the vase. They keep it intact while still allowing it to hold flowers.
Supported by the Parkinson’s Foundation Impact Award, Dr. Versées, and his lab at the Flanders Institute for Biotechnology in Belgium, will run a battery of biochemical experiments to hone the design of GCase-stabilizing nanobodies. First, he will use state-of-the-art molecular imaging techniques to see exactly where these nanobodies stick to GCase and how it affects the protein. This information will help Dr. Versées and his team identify which set of nanobodies are the best suited for clinical use and how he can further improve their effectiveness.
Collaborating with Steven Ballet, PhD, at Vrije Universiteit Brussel, they will also design so-called “peptidomimetics” that are inspired by the nanobodies and have similar GCase-stabilizing features. Since these are much smaller, they can be more easily delivered to the correct cells in the brain, acting as prototypes for future therapeutics.
Finally, working with Nicoletta Plotegher, PhD, at the University of Padova in Italy, Dr. Versées will test the effectiveness of these nanobodies and peptidomimetics in PD-simulated cells in the lab. Monitoring to what extent the mutant GCase proteins are stabilized and activated with these treatments will validate their potential for future research and their potential as a future treatment.
Excited by this support, Dr. Versées said “Receiving this award from the Parkinson’s Foundation is both a personal honor and a meaningful endorsement of our research. If successful, this strategy could lead to a new class of molecular chaperones that more effectively target the underlying molecular causes of Parkinson’s, opening new therapeutic avenues for people living with GBA1-associated PD.”
