2022 Stanley Fahn Junior Faculty Award  

Targeting the PARP1 Enzyme to Halt Parkinson’s Progression

Tae-In Kam, PhD, of Johns Hopkins University School of Medicine, a Parkinson’s Foundation Center of Excellence, received a Parkinson’s Foundation Stanley Fahn Junior Faculty Award to study the role of an enzyme called PARP1 in Parkinson’s disease (PD). An enzyme is usually a protein that alters how brain cells communicate. The goal is to halt the progression of Parkinson’s through exploring different mechanisms that target this enzyme.

The brain chemical dopamine is responsible for smooth, controlled movements. When the brain cells that produce dopamine die at a fast pace, early Parkinson’s movement symptoms occur — including rigidity and balance issues. All people with Parkinson’s have a low level of dopamine. Currently there are no treatments that prevent the progression of the disease.

A protein called alpha-synuclein is involved in the loss of dopamine brain cells. In Parkinson’s, alpha-synuclein misfolds and forms deposits in the brain. These deposits disrupt the brain’s normal functioning in people with PD. How exactly this protein causes Parkinson’s to progress is still unknown.

Dr. Kam recently found that in Parkinson’s, alpha-synuclein activates an enzyme called PARP1. Essentially, the enzyme sends toxic signals to brain cells, leading to cell death. How this occurs is not known.

In a mouse model, Dr. Kam will study PARP1’s role in the development of Parkinson’s, looking to identify compounds that affect the enzyme’s role in damaging nerve cells in Parkinson’s. These compounds could be a new target for future PD treatments.

“Our long-term goal is to discover treatments that impact PARP1, as well as discovering biomarkers to help diagnose PD,” Dr. Kam said. “This approach should have a significant impact on slowing or halting the degenerative process of PD and related diseases.”

Of his Parkinson’s Foundation grant award, he said, “This award will enable us to open new research horizons.”

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

2021 Postdoctoral Fellowship
2022 Launch Award

Understanding the Blood-Brain Barrier’s Role in Parkinson’s Disease

Aurélie de Rus Jacquet, PhD, of CHU de Québec-Université Laval, received a Parkinson’s Foundation Launch Award to study molecules (or cells) that can affect the blood-brain barrier and thus contribute to Parkinson’s disease (PD).

“The Launch Award will enable me to investigate the role of the blood-brain barrier and brain-blood communication in the onset and development of Parkinson’s,” said Dr. de Rus Jacquet. “We hope to identify factors on either side of the blood-brain barrier that interfere with its proper functioning in Parkinson’s. These factors could become drug targets.”

In the brain and body, Parkinson’s disease:

• Decreases the rate of certain brain cells.
• Causes an increase in inflammatory signals in the bloodstream.
• Makes PD-related protein called alpha-synuclein more toxic in the brain.
• Increases production of antibodies that recognize alpha-synuclein.

Cells in the brain are protected by a specialized security system called the blood-brain barrier. This is a network of blood vessels that allows the entry of essential nutrients while blocking other substances. People with Parkinson’s disease progressively lose this protection. When this happens, toxins and immune cells from outside the brain can enter the brain and speed disease progression. Researchers do not know what causes this. Loss of the barrier’s protection could be induced by toxic signals in the blood. It also could be caused by an inability of brain cells to maintain a strong barrier.

In her research, Dr. de Rus Jacquet will use complex state-of-the-art Parkinson’s models. She established a 3-D model of the blood-brain barrier using cells generated from both people with and without a PD-related gene mutation.

"Opening a new laboratory as an early career scientist will be an exciting adventure. I will face many challenges. but this Parkinson’s Foundation grant will greatly facilitate my success."

She will focus on brain cells called astrocytes, which are essential for the blood-brain barrier to efficiently function. She has found that Parkinson’s astrocytes are not able to form a strong barrier. Dr. de Rus Jacquet will test whether this leads to immune cells infiltrating the brain side of her model, mimicking a key aspect of Parkinson’s.

In a second set of experiments, Dr. de Rus Jacquet will study how plasma proteins are involved in Parkinson’s. She will expose the “blood” side of the barrier to the plasma of donors with and without Parkinson’s. She will determine how this plasma affects barrier function. She will see which plasma proteins cross the blood-brain barrier to affect cell health.

Of her Parkinson’s Foundation grant award, Dr. de Rus Jacquet said, “The Launch Award will have a profound impact on my career and abilities to continue research on Parkinson’s disease. This award is a recognition of research excellence. It also financially supports the first two years of my future independent career. Opening a new laboratory as an early career scientist will be an exciting adventure. I will face many challenges. but this Parkinson’s Foundation grant will greatly facilitate my success.”

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

Explore more of Dr. de Rus Jacquet’s research

Aurelie de Rus Jacquet will be furthering her research for which she received a Parkinson’s Foundation research grant in 2021. Read about her Postdoctoral Fellowship for Basic Scientists research below.

What Role Does the Blood-Brain Barrier Play in Parkinson’s?

Postdoctoral Fellowship for Basic Scientists

Aurelie de Rus Jacquet, PhD of Université Laval, Québec (Canada), received a Parkinson’s Foundation Postdoctoral Fellowship grant to study molecules (or cells) that could promote dysfunction in a specialized vascular system called the blood-brain barrier. People with Parkinson’s disease progressively lose the blood-brain barrier’s protection, but it is not currently understood why.

This barrier controls the crossing between the blood and the brain, and prevents toxic molecules found in the blood from entering the sensitive brain tissue and damaging cells.

The goal of this research is to identify factors on either side of the blood-brain barrier that could become targets for new drug treatments for PD.

“Most of the past research in the field has focused on understanding why neurons die over the course of the disease, but it is becoming clear that Parkinson’s disease is more complex than the loss of neurons,” said Dr. de Rus Jacquet. “Non-neuronal cells are also involved, and they could hold the key to understanding the global events underlying Parkinson’s disease onset and progression.”

Dr. de Rus Jacquet continued, “The second objective of the research is to understand if the blood of people with Parkinson’s disease contains toxic molecules that enter the brain and induce a loss of neurons and inflammation of the brain tissue. This topic is relatively less studied, but I find it fascinating because it could help identify new drug targets to slow or stop disease progression.”

Dr. de Rus Jacquet has established a 3D model of the blood-brain barrier using cells generated from healthy donors or people with a specific Parkinson’s disease-related gene mutation. She hopes to discover if non-neuronal cells or blood-borne factors may be responsible for the loss of neurons, and if targeting these cells could possibly help combat neurodegeneration.

“This award is an important recognition that my work can have a meaningful impact on the lives of people with Parkinson’s,” said Dr. de Rus Jacquet. “I would like to thank all Parkinson’s Foundation supporters for helping us move the research forward. Finding a cure for Parkinson’s disease and improving people’s lives is at the heart of what we do, and we can only achieve these goals by working together.”

2022 Postdoctoral Fellowship 

Targeting A Protein Involved in Dopamine Regulation Could Improve Effectiveness of Levodopa

Meghan Bucher, PhD, of Columbia University Medical Center, a Parkinson’s Foundation Center of Excellence, received a Parkinson’s Foundation Postdoctoral Fellowship for Basic Scientists to identify compounds that treat the movement symptoms of Parkinson’s disease (PD), either alone or in combination with levodopa. The goal is to improve the effectiveness of PD treatment.

There is no cure for Parkinson’s disease or treatment that slows the progression of the disease. PD treatments are tailored to every person’s individual symptoms. Treatment options can be a combination of physical therapy, exercise, medication and others. Levodopa is the go-to PD medication that treats movement symptoms, but may become less effective over time. As a result, new approaches to treat Parkinson’s disease are desperately needed.

The brain chemical dopamine is responsible for smooth, controlled movements. When the brain cells that produce dopamine die at a fast pace, the movement symptoms of Parkinson’s begin to occur — including rigidity and balance issues. A protein called synaptic vesicle glycoprotein 2C (SV2C) helps the brain regulate dopamine transmission. Its expression is enriched in the areas of the brain affected by PD.

In previous studies, SV2C has been identified as a risk factor for developing PD. It has also been found to affect how people with Parkinson’s respond to symptom relief from levodopa.

“My goal is to develop and screen novel compounds that will target SV2C activity,” said Dr. Bucher. “This research will determine their benefits in treating people with Parkinson’s.”

Dr. Bucher will investigate whether SV2C is a target for treatment that could alleviate movement symptoms and halt or slow disease progression. She will also evaluate whether a treatment targeting the protein could improve the effectiveness of levodopa when it comes to minimizing PD symptoms.

She has developed a lab test to evaluate compounds that could regulate SV2C activity. She will then use several Parkinson’s models to evaluate the compounds’ effect on dopamine transmission.

Of her Parkinson’s Foundation grant award, Dr. Bucher said, “The support of the Parkinson's Foundation will facilitate my transition into an independent investigator. It will allow me to continue my intellectual pursuit researching both the causes of and treatments for Parkinson's disease.”

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

2022 Postdoctoral Fellowship 

Creating A Diagnostic Test Could Detect Parkinson’s Earlier

Giovanni Bellomo, PhD, of the University of Perugia received a Parkinson’s Foundation Postdoctoral Fellowship for Basic Scientists to improve the usefulness of a group of testing techniques called seed amplification assays (SAAs) in the early diagnosis of Parkinson’s disease (PD).

There is no single test to diagnose Parkinson’s disease. A movement disorder specialist often heavily relies on the presence of movement symptoms to make a diagnosis. However, these symptoms appear several years after changes start occurring in the brain. This means that by the time symptoms appear, the disease is already past its early phase. Early detection would allow earlier disease-modifying treatment, which could potentially benefit people with PD.

One of the earliest known changes in the brain that occurs in PD is the deposits of a protein called alpha-synuclein. These deposits can spread among brain cells and trigger changes in the brain that lead to Parkinson’s. Seed amplification assays have been successfully used to detect alpha-synuclein pathological changes in the cerebrospinal fluid (CSF) of people with Parkinson’s.

Tests like the seed amplification assays are used to detect a biomarker (a biological molecule that is a sign of disease). Having a biomarker for Parkinson’s could lead to earlier diagnosis and can improve outcomes for people living with PD.

Cerebrospinal fluid circulates around the brain and spinal cord. “Currently, alpha-synuclein SAA is the most promising technique for the biomarker-based diagnosis of PD, even at early stages,” said Dr. Bellomo. “However, several factors limit their use in clinical practice.”

First, collecting CSF is an invasive procedure. Second, there are still no standards for SAA. This results in disparities among different labs using the technique. Finally, the results of SAA testing do not provide enough detailed information to use in monitoring treatment.

“This research will improve the usefulness of SAAs in obtaining a specific and early diagnosis of PD. This is crucial for properly planning a treatment approach and including people with PD in clinical trials,” said Dr. Bellomo.

First, Dr. Bellomo will study whether olfactory mucosa can be used in SAA. Early PD-related alpha-synuclein alterations can be found in the olfactory mucosa. Collecting this sample is easily achieved by using a swab to scrape small amounts of olfactory mucosa from inside the nose.

The researcher will compare the results of SAAs in CSF and olfactory mucosa collected from people with and without PD. This non-intrusive test would represent a breakthrough in Parkinson's diagnosis, as no such test currently exists.

Second, Dr. Bellomo also aims to improve current CSF SAAs by making them capable of estimating the amount of disease-causing alpha-synuclein present in CSF samples. This is a key step toward testing treatments against pathological forms of alpha-synuclein. In addition, it will show how these estimates relate to PD symptoms.

Of his Parkinson’s Foundation grant award, he said, “This award means a lot to me. As the son of a person with Parkinson's, it will give me the opportunity to make a significant contribution in the field of Parkinson's disease diagnostics.”

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

2024 Launch Award  

Investigating How Gut Bacteria May Influence Levodopa Effectiveness 

For most people living with Parkinson’s disease (PD), the medication levodopa plays a critical role in their daily lives. While levodopa does not treat the causes of PD, it does provide relief from movement symptoms, restoring precious agency and quality of life. Unfortunately, for some people with PD, levodopa is not effective at managing symptoms, though the reasons for this are not well understood.  

Christine Olson, PhD, recipient of a Parkinson’s Foundation Launch Award and a previous Postdoctoral Fellow, suspects that a certain type of bacteria living in the gut may be a root cause. She will be investigating this suspected strain in hopes of discovering ways to use targeted antibiotics to improve levodopa use for all who need it. 

Levodopa works by providing the brain with an extra source of dopamine, the neurotransmitter important for movement whose levels gradually decline throughout PD. The pills dissolve in the gut, where the levodopa molecules are absorbed and then shuttled by blood to the brain. Once in the brain, the levodopa is metabolized, or biochemically processed, into dopamine. 

Why not just give people dopamine pills?  

Due to its structure, dopamine cannot cross the blood-brain barrier, an important biological border that is selective about what may enter the brain for protection. Levodopa is designed so that it can pass that barrier, making it an excellent way to bring proto dopamine to the brain. 

Levodopa only works if it remains unmetabolized before it reaches the brain, therefore it is often prescribed along with carbidopa, a drug that inhibits the human proteins in the body that could process it prematurely.  

Dr. Olson, working in Dr. Peter Turnbaugh’s laboratory at the University of California, San Francisco, CA, a Parkinson’s Foundation Center of Excellence, recently discovered that Enterococcus faecalis (E. faecalis for short), one of the countless types of bacteria that can live in the guts of mammals, can also metabolize levodopa. This prompted her to think that maybe people with a higher amount of this bacteria in their gut have worse experiences with levodopa. 

First, Dr. Olson will utilize stool samples from people with PD collected in a clinical study looking at how using rifaximin, an antibiotic for irritable bowel syndrome which can reduce E. faecalis levels in the gut, impacts disease symptoms and treatment effectiveness. She will extract and grow the bacteria from those samples in petri dishes as a simulation of the bacteria population living in each participant’s gut and see how well they can metabolize levodopa. 

Dr. Olson will then compare that data to the participants’ health reports, seeing if those with more of levodopa-processing bacteria reported have a harder time with their PD symptoms than the others. 

Next, Dr. Olson will use laboratory mice to investigate the biochemistry behind E. faecalis’ effects on levodopa treatment, particularly: 

1. How antibiotics like rifaximin change the ability of the gut to absorb levodopa, and if the changes are influenced by levels of bacteria like E. faecalis 

2. Determine if neuron changes and degradation in mice with PD-like conditions can be prevented with antibiotics like rifaximin. 

Using a wide variety of tests and measurements, Dr. Olson will shed light on the specific mechanisms behind bacteria’s potential interference with levodopa, guiding advances to the medication that could improve and expand its use for all those that benefit from it. 

Asked about what the Parkinson’s Foundation award means to her and what her research means to the PD community, Dr. Olson said: “Receiving this award is a vote of confidence for the potential impacts of our work to help people with Parkinson's. By evaluating whether, and to what extent, gut bacterial drug metabolism pathways contribute to patient drug response, clinicians may better target treatments tailored to every individual.” 

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

Explore More of Dr. Olson’s Research

Christine Olson, PhD, is currently furthering her research regarding the gut and Parkinson’s for which she received a Parkinson’s Foundation Postdoctoral Fellowship research grant in 2022. Read about her prior research grant below.

Preventing Intestinal Bacteria from Breaking Down Levodopa May Improve PD Symptoms

Christine Olson, PhD, of the University of California, San Francisco, received a Parkinson’s Foundation Postdoctoral Fellowship for Basic Scientists to study whether reducing an intestinal bacteria that interferes with the absorption of the Parkinson’s disease (PD) medication levodopa may improve PD symptoms.

“Our research could expand our understanding of how gut microbes contribute to Parkinson's disease drug response and progression,” said Dr. Olson. “It could increase understanding of how people with PD respond to treatment. The findings may help clinicians better target treatments tailored to the individual. In addition, we may better be able to explain why people with PD have variable drug responses.”

Parkinson’s symptoms can often be successfully managed with levodopa treatment. However, many people with Parkinson’s have limited treatment success or negative side effects. The reasons for varied reactions to levodopa treatment are unknown.

Recent research highlights that the trillions of bacteria in the human gut can significantly change how treatments like levodopa are absorbed. This also means the microbes in the gut may impact how effective levodopa can be to people with Parkinson’s.

Dr. Olson’s postdoctoral lab found that a common gut bacterium has an enzyme that may lessen levodopa’s effectiveness. Prior work in the lab found that this bacterial enzyme reduced the amount of levodopa absorbed in an animal model. These data suggest that the breakdown of levodopa caused by gut bacteria may reduce drug absorption and treatment effectiveness in people with Parkinson’s. It is possible that variations in people’s gut bacteria contribute to differences in treatment response.

Dr. Olson will evaluate whether antibiotic-induced reductions in gut bacteria lead to improvement in Parkinson’s symptoms. She will also:

• Evaluate control of enzymes in the gut that lead to breakdown of levodopa.
• Test whether a drug that can inhibit levodopa breakdownin the gut affects movement symptoms.
• Test which gut bacteria and which bacterial genes may interfere with levodopa metabolism.

Dr. Olson’s lab also has an ongoing clinical trial where people with Parkinson’s are either treated with a mild antibiotic or a placebo. She will test intestinal microbe samples from participants with PD before and after treatment. This will show which bacteria are changing in response to the antibiotic.

“We will test for the first time whether models of Parkinson’s disease and people with Parkinson’s have improved symptoms after reduction of bacterial levodopa breakdown,” Dr. Olson said.

“This research may lead to novel ways to improve Parkinson’s disease treatment strategy.”

Of her Parkinson’s Foundation grant award, Dr. Olson said, “I am honored to receive this award in support of our Parkinson's disease research. Receiving this award is a vote of confidence for the potential impacts of our work for people with Parkinson's. Additionally, this award will help support my professional development and academic career.”

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

2022 Postdoctoral Fellowship 

Therapy That Targets QA Protein Could Lead to New Treatment for Parkinson’s

Kimberly Meyers, PhD, of the Barrow Neurological Institute, a Parkinson’s Foundation Center of Excellence, received a Parkinson’s Foundation Postdoctoral Fellowship for Basic Scientists to study whether a therapy that targets a protein called ACMSD can reduce brain inflammation and prevent the loss of brain cells.

“I am interested in understanding the molecular mechanisms of Parkinson’s and developing interventions for the disease,” said Dr. Meyers. The findings could be a first step in developing a new treatment for Parkinson’s disease (PD).

Parkinson’s is characterized by the misfolding of a protein called alpha-synuclein, which causes the protein to form deposits (or “build-up”) in the brain, contributing to inflammation. This causes the activation of a metabolic pathway called the kynurenine pathway in brain cells, which then produces molecules that cause toxicity of brain cells.

The overall result can be the accumulation of QA, a toxic metabolite of the kynurenine pathway that increases inflammation and leads to damage of brain cells. Increased QA levels have been detected in the brain and spinal fluid of people with Parkinson’s —higher QA levels are linked to worse Parkinson’s symptoms.

Dr. Meyers’ lab recently discovered that increased levels of the protein ACMSD can lead to reduced levels of the toxic protein, QA.

“We will use gene therapy to produce excess ACMSD in a susceptible brain region in an animal model of Parkinson’s,” said Dr. Meyers. “We will find out whether ACMSD therapy will reduce brain inflammation and prevent loss of brain cells. This research represents an important first step in developing a novel way of treating PD.”

Of her Parkinson’s Foundation grant award, Dr. Meyers said, “I am very excited to have received this prestigious fellowship. These funds will allow me to establish myself early in my career as an independent researcher. They place me on the path towards becoming a principal investigator in the field of PD. I am looking forward to using these funds to advance our results towards developing a novel intervention for PD.”

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