Building a Toolkit to Study Early-Onset Parkinson’s Genes in Rat Models
Genetic variants of the genes PRKN and PINK1 are the most common causes of young-onset Parkinson’s disease (PD). These two genes help create proteins, Parkin and Pink1, that maintain healthy mitochondria, the powerhouses of cells. PD-associated variants of these genes lead to impaired mitochondria maintenance and recycling, contributing to the progressive loss of dopamine-producing neurons in the brain.
Research into PRKN- and PINK1-associated PD has been difficult since mice—the most common animal model for research—with loss of function genetic variants do not exhibit PD-like disease symptoms. This has made it challenging to evaluate therapeutic treatments for PD cases resulting from genetic variants of these genes.
Kelly Stauch, PhD, recipient of a Parkinson’s Foundation Impact Award, is building out tools so that researchers can better use rats to study mitochondria health in PD. Unlike mice, rats with loss of function PRKN and PINK1 variants develop PD-like neurodegeneration and symptoms, making them more effective animal models for studying these genes.
“The tools developed as part of this award will aid my PD research as well as others in the field by providing a method to study cell type-specific mitochondria in non-mice models of PD." – Dr. Stauch
Working out of the University of Nebraska Medical Center in Omaha, Dr. Stauch will utilize a molecular tag that lets her microscopically visualize mitochondria in rat neurons. Co-created with her collaborator Ian Ganley, PhD, this mitochondria tag will establish new data on how Parkin and Pink1 proteins influence mitochondria health and recycling.
Dr. Stauch will then use a similar mitochondria tag to measure how Parkin and Pink1 disruption affects the function of mitochondria and their recycling in cells. Mitochondria naturally wear out over time, so the ability to disassemble them and make new mitochondria is essential for cell health. Using these tagging tools and looking at PD-related dopamine neurons in rat brains, Dr. Stauch will expand our biological understanding of Pink1 and Parkin-related PD, contributing to future research and treatment development.
“This award will allow me to complete this innovative project, which will enable a new approach for studying mitochondria in nigrostriatal dopaminergic neurons in rat models of PD,” said Dr. Stauch. “Further, the tools developed here could be used in other PD rat models as well as adapted to other non-rodent models in the future.”
Investigating Which Brain Signals Best Guide Adaptive Deep Brain Stimulation
Deep brain stimulation (DBS) is a promising treatment option for those with Parkinson’s disease (PD) when medications begin to lose their effectiveness. For DBS, electrodes are implanted into the brain that deliver controlled electrical stimulation that counteracts the PD symptoms.
Most DBS systems are designed to deliver constant, consistent stimulation based on settings set and updated by physicians during checkups. However, a newer version called adaptive DBS (aDBS), recently approved by the 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.
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.
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 their 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.
When asked what this support means to her and her research goals, Dr. Hammer said “Receiving this award is an incredible honor and an important milestone in my journey to improve the lives of people with Parkinson’s disease. This research could support expanding the set of neural signals used for clinical aDBS, enabling more effective and personalized treatment.”
Branching Out Toward New Parkinson’s Therapies by Studying the Brainstem
In Parkinson’s disease (PD), specific dopamine-producing neurons in the brain degenerate over time and lead to progressive movement and cognitive symptoms. A multitude of therapeutic research has focused on the impact of losing these neurons on connections within the brain, which has helped develop treatments like dopamine replacement therapy (DRT) and deep brain stimulation (DBS).
While generally effective, these therapies have their limitations and side effects, prompting investigation into alternative treatment strategies. Jared Cregg, PhD, recipient of a Parkinson’s Foundation Stanley Fahn Junior Faculty Award, is exploring how modulating a different area of the brain, the brainstem, could provide new therapeutic potential for those with PD.
The loss of dopamine in PD rewires the circuitry of the brain in several regions critical for movement. Many of these brain areas are highly “plastic,” meaning that they are prone to being rewired, particularly in a disease like PD. However, the circuits within the brainstem produce stable, reflexive motor actions, and Dr. Cregg hopes to leverage the stability of these connections to help restore movement to people with PD.
“This work aims to establish a new framework for treating movement impairments in Parkinson’s disease by shifting focus from traditional targets to the brainstem circuits that naturally govern locomotion.” – Dr. Cregg
From his lab at the University of Wisconsin – Madison, where he is an assistant professor of neuroscience and neurology, Dr. Cregg will first create a biochemical map of two brainstem regions known as the pedunculopontine nucleus (PPN), which regulates movement speed, and the rostral pontine reticular formation (PnO), which regulates turning. This map will then help him to develop tools to selectively target specific neurons in those regions that control these movements in mice.
These tools will enable Dr. Cregg to stimulate these neurons at will. By testing these tools in mice that have Parkinson’s-like symptoms, he can see the potential effects of future therapies that target the brainstem in a similar way. The scientific knowledge gained from these experiments will guide future brainstem-centered PD treatments.
When asked about what this support means to him and his work, Dr. Cregg said “Receiving this award is an incredible honor and a meaningful endorsement of our efforts to chart a new path in Parkinson’s research. By refining these brainstem-based therapies, this work could pave the way for more stable, long-lasting interventions that improve movement in people with PD.”
Scanning Healthcare Data to Improve Earlier Detection and Diagnosis of PD
Parkinson’s disease (PD) can be difficult to diagnose by clinicians, especially in early stages of the disease. This means that some people with PD may get diagnoses only late in the disease when the symptoms are more obvious. Others may never get a formal diagnosis at all.
Jacob Simmering, PhD, recipient of a Parkinson’s Foundation Stanley Fahn Junior Faculty Award, is digging through healthcare data to find clues that could lead to earlier and more accurate diagnoses of PD. Using statistical analysis, he hopes to identify diagnostic patterns that commonly precede PD and that could be used as future medical signposts, guiding doctors toward earlier detection of the disease.
“This research will enable us to improve the timeliness of detection and diagnosis of Parkinson's disease.” – Dr. Simmering
From his lab at the University of Iowa, a Parkinson’s Foundation Center of Excellence, Dr. Simmering is utilizing health insurance databases to collect healthcare data on nearly 250,000 deidentified people recently diagnosed with PD. From this information, he hopes to identify a “diagnostic window” for PD—a stretch of time with repeated doctor’s visits for PD-like symptoms signaling the presence of the disease.
Dr. Simmering will then use this diagnostic window as a frame, looking at people with recent diagnoses and figuring out what prevented physicians from diagnosing PD sooner. His hypothesis is that the three biggest factors that play into delayed diagnoses are:
Unique symptom patterns of PD
Living in more rural areas
Not being seen by a neurologist
Sorting through this data will provide evidence for other repeated symptoms that could clue doctors into a PD diagnosis earlier. While tremor and involuntary movements are most commonly used to lead to a PD diagnosis, other symptoms like urinary problems and anxiety could be just as valuable. Altogether, Dr. Simmering will use this detailed analysis to generate a forward-looking “risk score” to identify people who are most at risk of developing PD.
“These results will allow us to screen for people who have symptoms and characteristics similar to people who will go on to be diagnosed with Parkinson's disease, potentially allowing for earlier detection of disease,” said Dr. Simmering.
Earlier detection means providing symptom relief sooner to those with the disease, improving their quality of life with early treatment.
Parkinson’s Foundation Shares Six Scientific Posters at International Congress of Parkinson’s Disease and Movement Disorders
Every year, thousands of neurologists, researchers and other Parkinson’s disease (PD) experts gather at the International Congress of Parkinson’s Disease and Movement Disorders to share new ideas and breakthroughs aimed at transforming life for people with Parkinson’s. This year the conference took place October 5 in Honolulu, HI.
1. Returning Secondary Health Findings in the PD GENEration Study
PD GENEration: Powered by the Parkinson’s Foundationis a global research study providing genetic testing and counseling at no cost to people with Parkinson’s. Since 2019, the study has expanded to nearly 70 sites in the U.S. and internationally, enrolling more than 27,000 participants. PD GENEration also recently expanded its testing platform to provide secondary health findings to participants.
Using whole genome sequencing that looks at a person’s entire DNA, PD GENEration can now disclose 21 genes linked to either PD or parkinsonism and 10 non-PD related genes.
Key Takeaways
As of February 2025, 96% of study participants with whole genome sequencing consented to receive secondary health findings.
Gene-specific counseling materials were created to share this additional genetic health information with participants. A system was also established to review genes of secondary health findings as new research emerges.
Future studies will help researchers better understand how people feel after receiving these results.
2. Engagement of PD GENEration Participants: Insights into Genetic Counseling Recall and Clinical Trial Interest
Previously, data for PD GENEration was only collected from participants at enrollment — this limited long-term insights. The Parkinson’s Foundation followed up with participants to better understand their PD GENEration experience and whether their views on joining the clinical research trial changed over time.
Key Takeaways
While most respondents remembered their PD GENEration experience and many were interested in learning more about future clinical trials, nearly 30% either did not recall receiving genetic counseling or receiving their genetic test report.
People who had a negative test result or a longer enrollment period were slightly more likely to misremember their PD GENEration experience. Men were also slightly more likely to misremember than women.
The results emphasize the importance of developing methods for ongoing engagement and information sharing.
3. Distribution of Genomic Ancestries and Genetic Variation Among Individuals Enrolled in the PD GENEration Study
Analyzing genetic ancestry is important in large Parkinson’s genetic studies to accurately measure PD risk in different populations. This study looked at the genetic backgrounds of people in the PD GENEration study and how often certain genetic results were found.
As of August 2025, next-generation genetic sequencing — which allows for comprehensive analysis of genetic variations — was completed for 22,189 people with Parkinson’s. Of those tested, about 12% were found to have a genetic change linked to the disease. Most of those tested have European genetic ancestry, and more than 9% are of Ashkenazi Jewish genetic ancestry.
Key Takeaways
There were differences between what participants reported as their race, ethnicity and ancestry and what the genetic test results showed.
The study also showed that the likelihood of having specific Parkinson’s-related genes varies depending on a person’s genetic ancestry.
The high number of people with European ancestry in PD GENEration is driving efforts to recruit participants from diverse ancestries to better understand how genes affect disease risk.
4. The Role of Research and Genetics Educational Events in Parkinson’s Research: Overcoming Barriers in the Hispanic/Latino Community
Diversity in Parkinson’s research is key to understanding the disease and discovering new treatments. Hispanic and Latino members of the Parkinson’s community remain underrepresented in genetics research due to barriers such as language differences, lack of information and unequal access to healthcare.
A 2024 strategic collaboration between the Parkinson’s Foundation and the Latin American Research Consortium on the Genetics of Parkinson’s Disease (LARGE-PD) expanded PD GENEration genetic testing and counseling across Latin America to increase Hispanic and Latino participation in genetic research.
Educational outreach events in Mexico City, Mexico and Cali, Colombia staffed by local doctor and nurse volunteers combined on-site participant recruitment with information on research, genetics and broader community topics. These events included tailored Spanish-language materials.
Key Takeaways
Sustained, community-driven efforts are key to addressing participation gaps among medically underrepresented communities.
Research and genetics educational events, along with culturally adapted recruitment strategies, can reduce barriers, raise awareness and boost Hispanic and Latino participation in Parkinson’s genetic research.
The share of Hispanic and Latino PD GENEration participants rose sharply in September 2024, reaching a peak of more than 35%, reflecting recruitment efforts.
5. Online Learning Preferences of Healthcare Providers Caring for People with Parkinson’s
Many health professionals are required to continue their education to stay current with evolving knowledge and research. This learning can often be done online. However, information on how healthcare professionals caring for people with Parkinson’s prefer to learn online is limited. This study aimed to identify continuing education learning preferences and barriers to course participation and completion across nearly 5,000 healthcare professionals caring for people with PD.
Key Takeaways
Participants preferred live and recorded webinars as well as interactive and hands-on learning experiences that are directly relevant to their healthcare roles.
This study showed time and financial constraints can be barriers to continuing education. Course workload and media playback speed can also be factors that can affect completion rates.
The Parkinson’s Foundation will use these results to inform the development of future online continuing education for healthcare professionals.
6. Parkinson’s Exercise Guidelines: From Outdated to Updated
Exercise and movement can improve many Parkinson's symptoms. The Parkinson’s Foundation, in collaboration with the American College of Sports Medicine, created Parkinson’s exercise recommendations in 2021 to help people with PD receive safe and effective exercise. Clinical guidelines are typically reviewed and updated every three to five years to ensure they reflect the latest, high-quality, evidence-based care. The Parkinson’s Foundation conducted research to identify any gaps in literature and used its findings to revise professional-facing exercise recommendation guidelines. A panel of international subject matter experts and people with Parkinson’s reviewed the revisions. Their feedback, along with information collected during a public comment period, was used to further improve the guidelines.
Key Takeaways
The panel agreed recommendations should highlight the importance of exercise safety, a referral to a physical therapist and exercise modifications based on the ability of the person with Parkinson’s, their medication status and their stage of PD.
The guidelines were updated to reflect input from the panel, the public and the latest evidence and best practices.
The Parkinson’s Foundation turned the guidelines into a practical, user-friendly guide for exercise professionals who work with people with Parkinson’s.
Meet a Researcher Aiming to Improve Early Detection and Diagnosis of PD
Parkinson’s disease (PD) can be difficult to diagnose by clinicians, especially in early stages of the disease. This means that some people with PD may get diagnoses only late in the disease when the symptoms are more obvious. Others may never get a formal diagnosis at all.
Jacob Simmering, PhD, recipient of a Parkinson’s Foundation Stanley Fahn Junior Faculty Award, is digging through healthcare data to find clues that could lead to earlier and more accurate diagnoses of PD. Using statistical analysis, he hopes to identify diagnostic patterns that commonly precede PD and that could be used as future medical signposts, guiding doctors toward earlier detection of the disease.
“This award is crucial to my career development as a researcher in Parkinson’s disease,” said Dr. Simmering. “Parkinson’s disease is a common neurodegenerative disease without any disease-modifying, neuroprotective therapies. One issue with degenerative diseases is that the damage is irreversible. By the time clinical symptoms become apparent, the disease is often very advanced in terms of neuronal death. Earlier intervention may allow for treatments that preserve neurons — slowing, if not preventing, progression.”
From his lab at the University of Iowa, a Parkinson’s Foundation Center of Excellence, Dr. Simmering is utilizing health insurance databases to collect healthcare data on nearly 250,000 deidentified people recently diagnosed with PD. From this information, he hopes to identify a “diagnostic window” for PD—a stretch of time with repeated doctor’s visits for PD-like symptoms signaling the presence of the disease.
Dr. Simmering will then use this diagnostic window as a frame, looking at people with recent diagnoses and figuring out what prevented physicians from diagnosing PD sooner. His hypothesis is that the three biggest factors that play into delayed diagnoses are:
Unique symptom patterns of PD
Living in more rural areas
Not being seen by a neurologist
Sorting through this data will provide evidence for other repeated symptoms that could clue doctors into a PD diagnosis earlier. While tremor and involuntary movements are most commonly used to lead to a PD diagnosis, other symptoms like urinary problems and anxiety could be just as valuable. Altogether, Dr. Simmering will use this detailed analysis to generate a forward-looking “risk score” to identify people who are most at risk of developing PD.
“These results will allow us to screen for people who have symptoms and characteristics similar to people who will go on to be diagnosed with Parkinson's disease, potentially allowing for earlier detection of disease,” said Dr. Simmering.
Earlier detection means providing symptom relief sooner to those with the disease, improving their quality of life with early treatment.
Mi nombre es Adriana Jiménez. Mi papá fue diagnosticado hace más de 10 años con la enfermedad de Parkinson y en ese momento empezó nuestra aventura con esta condición, ya que yo no sabía lo que significaba.
Mis papás están en la ciudad de Guadalajara y yo vivo en los Ángeles, Ca., y estar a distancia fue un reto bastante grande. Gracias a Dios, tuve la oportunidad de ir a verlos y ver que no había nada de información del Parkinson en Guadalajara. Cuando regresé a California, empecé a buscar información de lo que es esta enfermedad.
Al principio, no encontraba nada en español y logré contactarme con la Parkinson’s Foundation que, dándose cuenta de la gran necesidad de información en español que se requiere, ha tomado el liderazgo en crear documentos informativos.
En el 2018, pude asistir a la primera conferencia en español de la Parkinson’s Foundation en Long Beach, Ca., donde pude entender qué es esta condición, cuáles son las diferentes terapias y cómo hablar con mis papás y familiares para que pudieran entenderlo. ¡Ser un cuidador a distancia no es fácil! Sin embargo, tampoco la distancia es un impedimento para poder estar cerca de nuestra familia y apoyarla. ¡Buscar la información e instruirnos marca una gran diferencia!
Mi mamá fue diagnosticada también con Parkinson hace 4 años y la forma en que entendimos y la ayudamos fue diferente que a mi papá. Ya tenía más información. Pude explicarle lo importante de saber que cada persona con Parkinson es diferente y que, a pesar de estar lejos, siempre estoy con ellos, llevándoles nuevas clases en línea que encuentro en la Parkinson’s Foundation, contactando a mi mamá con doctores, creando grupos de apoyo, uniéndome con otras personas que están en la misma situación que la mía, con quienes compartimos las mismas preguntas e inquietudes.
Soy fiel creyente en que la unión hace la fuerza y ahí decidí crear el programa de Parkinson con Give for a Smile, donde encontré también doctores y especialistas hispanos, como yo, aquí en los Estados Unidos, que tienen un gran amor a nuestras familias latinas, a nuestras familias con Parkinson; porque siempre digo: no es una persona con Parkinson; ¡es una familia con Parkinson!
Con esta enfermedad, toda la dinámica cambia; pero si lo entendemos, lo procesamos y nos unimos, podemos marcar la diferencia en nosotros, en nuestra familia y en nuestra comunidad.
Si me preguntara, ¿qué me hace feliz en esta aventura del Parkinson? Puedo decir tranquilamente que saber que, aun a la distancia, puedo estar cerca de mis papás, ayudándolos con información, clases por Zoom, conferencias y a saber que tener Parkinson no es el final del camino; es el principio de una nueva aventura; que mi familia ha crecido, porque la familia del Parkinson me abraza y me apoya siempre. ¡Lo único que tengo que hacer es unirme a ella!
Mainstay Parkinson's Medication Sometimes "Wears Off" Faster for Women
Levodopa, which helps with the movement symptoms of Parkinson’s, tends to work less well over time, especially for women.
Parkinson's disease (PD) is a condition that gets worse over time, impacting the nervous system. It's caused by the gradual death of brain cells that produce dopamine, a crucial chemical messenger for controlling movement. When these cells are lost and dopamine levels drop, people with Parkinson's begin to experience noticeable symptoms like shaking or tremors, muscle stiffness, a general slowness of movement and problems with balance.
A primary treatment for these movement symptoms is the drug levodopa. The body converts this medication into dopamine, helping to replenish the brain's supply. By doing so, levodopa can significantly reduce the physical challenges of the disease and improve a person's daily life.
However, for many individuals with Parkinson's, the effectiveness of levodopa can begin to diminish between doses. In other words, it starts "wearing off." Patients may notice their movement symptoms, such as tremors and stiffness, gradually returning before their next scheduled dose.
Parkinson’s also impacts men and women differently. Men are estimated to be 1.5 times more likely to develop Parkinson’s. Women with Parkinson's are often diagnosed at a later age and may have slightly different symptoms. These differences between men and women with Parkinson’s could be due to a variety of factors, including hormonal differences and genetics.
To better understand how these gender differences impact experience with levodopa, a recent study tracked 216 individuals with Parkinson's over a two-year period. The goal was to investigate whether men and women experience levodopa wearing off at different rates and to examine the symptoms that occur while on this medication.
Study Results
Participants included 139 men and 77 women with Parkinson’s who began taking levodopa for the first time at the start of the study. After two years in the study, almost 65% of women experienced symptom fluctuations, or times when the medication's effects seem to "wear off" before the next dose is due. This was compared to about 53% of men. This suggests that for many women, the medication was less effective in managing symptoms and did not feel as consistent over time.
In addition, more women in the study developed dyskinesia, a side effect of levodopa that leads to involuntary, uncontrolled movements. About 14% of women developed dyskinesia compared to only 5% of men. Taken together, these results suggest that there may be differences in how levodopa is processed in the body between men and women.
The study concluded that being female was the strongest predictor for both the wearing-off effect and dyskinesia after taking levodopa for two years. This indicates that gender is an important factor when considering how a person might respond to this medication.
Highlights
The study followed 139 men and 77 women with Parkinson’s for two years after they started taking levodopa for the first time.
During the two-year study period, 65% of women experienced times when the medication's effects seemed to "wear off" before the next dose. This was compared to about 53% of men.
During the study, about 14% of women developed dyskinesia, compared to only 5% of men.
The study concluded that female gender predicted the development of motor fluctuations and dyskinesia more than any other factor.
What does this mean?
Women’s experiences have been historically underrepresented in PD research. This study adds to increasing evidence that men and women often experience various aspects of PD differently, including in their response to the PD medication levodopa. Specifically, these results indicate that women may be more likely to have worse responses to levodopa treatment over time compared to men. However, the reasons for these differences between men and women are still unknown. Additionally, it is common for both men and women to have breakthrough symptoms on levodopa over time.
What do these findings mean to people with PD right now?
Knowing that men and women may react differently to prolonged levodopa treatment can help healthcare providers develop more effective treatment plans for patients. While more research needs to be done, the findings from this study suggest that more tailored, “gender-oriented” treatment recommendations may be needed. If you are struggling with symptoms related to levodopa treatment, talk to your doctor to discuss your treatment plan.
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.
Genetic variants of LRRK2 can be found in 1-5% of all PD cases. However, abnormal LRRK2 activity is often seen even in people without a clear genetic link to the disease, making the protein a strong target for designing novel treatments. Katy Surridge, PhD, recipient of a Parkinson’s Foundation Postdoctoral Fellowship, is broadening our understanding of LRRK2’s role in cells to improve PD treatment development.
Like nearly all proteins, LRRK2’s activity is regulated by switching between an “off/open” and an “on/closed” state. The majority of research and treatments are focused on drugs that target LRRK2’s “closed” form, but evidence suggests that the protein’s “open” form may be a better therapeutic target in cells. Understanding how the use of different drugs with different mechanisms of action affects LRRK2’s role in cells is important for understanding both the normal function of the protein, and how best to target it for PD treatment. Dr. Surridge, under the mentorship of Samara Reck-Peterson, PhD, at Weill Cornell Medicine in New York City, has recently created tools that allow her to target and observe both forms of LRRK2 in cells, something that has not been directly studied before.
“My research will use a newly designed toolkit of small molecules to study LRRK2’s endogenous interactome, localization, and the potential cellular consequences of therapeutic LRRK2 inhibition with different drug types” - Dr. Surridge
Using these tools, Dr. Surridge will first explore LRRK2’s interactome – the collection of all the other proteins in the cell that interact with LRRK2. She will compare and contrast which proteins interact with LRRK2 in its open state vs. its closed state, highlighting which processes would be affected during different types of LRRK2 treatments.
Next, Dr. Surridge will analyze the different pattern of modifications (phosphosites) on LRRK2 itself. Evidence suggests that LRRK2 is modified differently in its different forms, and she hopes that by mapping these differences, she will identify novel features which can be used in both diagnostics and the design of new ways to specifically target the protein in future therapies.
Dr. Surridge will then monitor how the protein’s localization within the cell changes depending on form. Previous studies have suggested that certain drugs may affect LRRK2’s localization in cells, and that this could impact other cellular processes. Dr. Surridge therefore expects to find closed-form LRRK2 in different parts of the cell than open-form LRRK2.
These experiments will empower researchers to see and study LRRK2 in completely new ways, unlocking paths to new LRRK2-centered treatments of PD. When asked about how she feels about the fellowship and her upcoming research, Dr. Surridge said “I am delighted to receive this award from the Parkinson’s Foundation, which will help me to address a critical gap in knowledge in the field of LRRK2 cell biology, with potential to inform the future design of novel Parkinson’s disease therapeutics.”
Creating Self-Folding Alpha-synuclein to Better Understand Parkinson’s
A primary driver of Parkinson’s disease (PD) is the accumulation and spread in the brain of a misfolded form of a protein called alpha-synuclein. When misfolded, alpha-synuclein forms clumps called Lewy bodies that clog up brain cells called neurons. These clumps can cause other alpha-synuclein proteins to misfold as well, cascading the disruption as the disease progresses.
Despite decades of innovation, conducting in vivo research (animal experiments, as opposed to cells in petri dishes) of alpha-synuclein in PD has been challenging. Getting alpha-synuclein to misfold in a way that mimics human PD in specific neurons on-demand is difficult, but Yujie Fan, PhD, recipient of a Parkinson’s Foundation Postdoctoral Fellowship, believes she has developed a new tool to accomplish this task.
Under the mentorship of Viviana Gradinaru, PhD, at the California Institute of Technology in Pasadena, Dr. Fan designed a new technology for creating what she calls “self-assembling alpha-synuclein" (SAS) molecules. These SAS constructs are made of normal alpha-synuclein with attachments that allow researchers to trigger misfolding in cells on-demand. The SAS technology also allows Dr. Fan to pick specific cells in which the misfolding occurs, such as the dopamine neurons in the brain most affected by PD. Importantly, this tool overcomes many of the limitations that have hindered other research models of alpha-synuclein in PD.
“This award supports the development of an innovative tool named self-assembling synuclein (SAS) to model Parkinson's disease in a quantitative, inducible, tunable and cell-type-specific manner.”
- Dr. Fan
Once the SAS tools have been fine-tuned and tested, Dr. Fan will implement them in mice to see if they can recreate alpha-synuclein misfolding and clumping like is seen in human PD. Her early results in mice show that the SAS model faithfully mimics many of the movement impairments commonly seen in people with PD, suggesting that her tools are working as expected. She will then test how alpha-synuclein misfolding in the gut might initiate PD-like symptoms, following recent research suggesting that PD could start in the gut.
Refining and building upon this SAS technology will grant Dr. Fan and other PD researchers the ability to study the disease in new, more precise ways. The groundbreaking data and insights generated from these SAS experiments can lead to improved treatments and advance the field toward a cure for PD.
Speaking on what this fellowship means to her and PD research broadly, Dr. Fan said “This award gives me the freedom and confidence to pursue bold, yet high-rewarding ideas. The insights gained from this work could help identify new treatment targets and improve how we test potential therapies. Ultimately, this research aims to bring us closer to stopping disease progression in PD.”
