Uncovering how an alternative mitochondria cleanup process may reduce brain inflammation
Inflammation is the body’s way of dealing with unwanted invaders, mobilizing immune cells to contain, destroy, and clean up areas of infection or injury. However, this process sometimes malfunctions, leading to cell and tissue damage. There is evidence to suggest that such inflammation misfires occur in Parkinson’s disease (PD) and may be contributing to neuron degeneration; however, the source of these potential inflammatory errors has not yet been identified. Tahnee Saunders, PhD, recipient of a Parkinson’s Foundation Postdoctoral Fellowship for Basic Scientists, believes that answer may lie in mitochondria, the powerhouses of the cell.
Mitochondria are organelles, or “mini organs,” found in nearly all cells that use oxygen to power numerous critical biological processes. Like any other hard-working engines, mitochondria eventually get worn out and may break down, requiring disposal by the cell in a process called mitophagy (from the Latin “phagus”, meaning “to eat”) that involves the proteins PINK1 and Parkin. In some cases of young-onset PD, those two mitophagy proteins are dysfunctional, preventing the disposal of broken mitochondria and potentially contributing to increased inflammation and neurodegeneration.
Dr. Saunders, working with her colleagues in the lab of Associate Professor Michael Lazarou at the Walter and Eliza Hall Institute in Victoria, Australia, will be investigating a new form of mitophagy that may hold therapeutic promise for those with PD involving mitochondrial damage. This form of mitophagy occurs when the inner mitochondrial membrane (IMM) becomes exposed and is used to start the disposal chain reaction independent of PINK1 and Parkin. Using cells from both PD-model mice and from people with PD, Dr. Saunders will define the key factors driving IMM-induced mitophagy while also exploring the prevalence of this pathway in different cell types found in the brain.
With the knowledge gained from this research, novel therapies may be developed that boost IMM-induced mitophagy in the brains of those with PD, including individuals with PINK1 or Parkin deficiencies, potentially reducing inflammation and consequent neuron loss. Such therapies could one day be life-changing to those with PD, slowing or even stopping the progression of the disease.
When asked what this Parkinson’s Foundation grant award means to her, Dr. Saunders said it “has been a huge validation of the work I am doing and has given me a clear vision for my future research into Parkinson’s disease…I feel extremely passionate about helping those living with Parkinson’s.”
Episode 156: Research Series: Expanding PD GENEration
Variants of several genes have been identified that raise the risk of developing Parkinson’s disease (PD). PD GENEration: Mapping the Future of Parkinson’s Disease is the Parkinson’s Foundation groundbreaking initiative that seeks to uncover the relationship between genetics and one’s risk for PD. The goal is to eventually help people better manage their disease, facilitate research into better treatments, and potentially, find a cure. The study is now expanding to actively enroll people of diverse backgrounds. Variants of certain genes associated with the risk of developing PD have different frequencies among different populations. Besides reaching out to Black and Asian communities in the mainland United States, PD GENEration is now expanding to Hispanic communities in Puerto Rico as well as in the Dominican Republic (DR).
Although every person’s disease is unique to them, understanding genetic differences across broad groups of people may help explain why a person’s experience with the disease differs from others. That is why it is important for PD GENEration to enroll people from diverse communities, where genes associated with the disease may occur at different frequencies.
Our guest in this episode is Amasi Kumeh, Director of Research Partnership at the Parkinson’s Foundation. She explains why it is important to include people of diverse backgrounds in the study and how and where the Foundation is reaching out to enroll people from a diverse range of communities in PD GENEration.
Released: August 8, 2023
Amasi Kumeh is the Director of Research Partnerships at the Parkinson's Foundation. She has worked in various capacities in the Parkinson's research sector for over ten years. She has experience as a global business process and program management expert for collaborative pre-clinical and clinical research projects related to Parkinson's disease. She is passionate about inclusivity and diversity in Parkinson's research to improve life for all people with Parkinson's and their family members. She currently spearheads a Foundation initiative to expand Parkinson's research into diverse communities and is responsible for cultivating industry partnerships to leverage the Foundation's rich data assets and increase investments in their flagship clinical programs.
Untangling the connections between inflammation, aging and Parkinson’s disease
Inflammation is a process that occurs in the body as a response to a threat (e.g., an injury or a wound). However, the body’s ability to wind down the response after the threat has passed decreases as the body ages. This results in a consistent low-level, age-related inflammation known as “inflammaging” that is thought to weaken cells and tissues, including the brain. As aging is the greatest risk factor for Parkinson’s disease (PD), many have hypothesized that inflammaging plays a role in the development and progression of the disease. The details and mechanisms behind such a connection have remained a mystery, but Sarah Talley, PhD, recipient of a Parkinson’s Foundation Postdoctoral Fellowship for Basic Scientists, is hoping to shed some light on the subject.
Dr. Talley, working in the lab of Dr. Edward Campbell at the Loyola University Medical Center in Chicago, IL, seeks to understand how inflammaging may exacerbate the spread of alpha-synuclein clumps in the brain. These tangled-up alpha-synuclein proteins have been directly associated with PD, causing progressive neurodegeneration as they spread from cell to cell. It has also been shown that mice experience inflammaging like humans, making them the model of choice for Dr. Talley’s research.
What is inflammaging? Inflammaging refers to consistent inflammation that
increases as a person ages. It can weaken cells and tissues, including the brain, and may play a role in PD progression.
The key to these experiments is a genetically modified mouse line, previously generated by Dr. Talley and her fellow researchers, in which key cell types in the brain light up when experiencing inflammation. This light – bioluminescence, more specifically – can be measured and quantified under a high-powered microscope, allowing Dr. Talley to quantify inflammation in different brain cell types over time. With sophisticated cranial window imaging techniques, she will be able to make these measurements while the mice are still alive, providing valuable data over time.
Dr. Talley will inject alpha-synuclein tangles into the brains of these mice and monitor how those tangles spread and cause damage in the brain over time, but also how that spread affects brain-wide inflammation. By conducting these experiments in both young (6-week-old) and old (18-month-old) mice, Dr. Talley will be able to compare inflammation changes and alpha-synuclein spread between the age groups.
Dr. Talley, excited for the chance to start this research with the support of the Parkinson’s Foundation, spoke to the significance of this project: “We finally have the tools in place to measure when and where inflammation occurs in the [brain] during Parkinson's disease development in mouse models of the disease… These experiments will provide foundational knowledge that can inform on when and where anti-inflammatory therapeutics could be used to remedy disease in PD patients."
Highlighting the Connections between Parkinson's, Immune Responses and the Gut
It is becoming clear that gut and brain health are intrinsically connected. This connection is referred to as the “gut-brain axis.” Parkinson’s disease (PD) is no exception. Several studies highlight how gastrointestinal issues, such as constipation, commonly show up before movement symptoms when it comes to PD — often by years or decades. While the pathways linking gut health specifically to PD progression are still unknown, Juliet Taylor, PhD, and recipient of a Parkinson’s Foundation Impact Award, believes that an important element involved is type-I interferon (IFN) signaling, a part of the body’s immune response toolkit.
From her lab at the University of Melbourne in Parkville, Australia, Dr. Taylor seeks to understand how early IFN disturbances in the gut may lead to later PD development, and whether affecting such signaling can slow or prevent overall disease progression.
Meet IFN. Even those well-versed in Parkinson’s may not be familiar with type-I interferon (IFN) receptors. IFN’s help the body fight infection. Parkinson’s Foundation researcher, Juliet Taylor, is investigating whether IFN issues in the gut may lead to later PD development, and whether affecting signaling can slow or prevent overall disease progression.
IFN proteins are secreted by white blood cells, often in response to infections to stimulate immune responses. The ability of IFNs to quickly drive the body to fight back against invaders has its risks, however, since prolonged or improper IFN signaling can cause major stress and damage to cells and organs. IFN regulation has been shown to be critical in the gut, where the intestinal walls constantly encounter and prevent infection by microbes.
Dr. Taylor and her team have recently discovered that lab-created gut organoids — three-dimensional collections of gut cells that can be used to mimic live tissue — injected with PD-associated alpha-synuclein clusters (the protein associated with PD) show increased IFN production. To better understand this immune reaction to alpha-synuclein in the gut, Dr. Taylor will create variations of gut organoids with and without IFN signaling receptors and see how they react to alpha-synuclein exposure, helping to determine which gut cell types are most important in the response.
Next, Dr. Taylor will examine how alpha-synuclein injected into the gastric (gut) walls of young and old mice affects overall gastrointestinal health as well as how it may spread to the brain to cause PD-like neurodegeneration and movement symptoms. She will also use genetically engineered mice that lack the IFN-receptors to further explore how that pathway is associated with PD progression along the gut-brain axis.
Speaking on how the Parkinson’s Foundation award will support her lab’s research goals, Dr. Taylor said, “While the majority of research has focused on the brain pathology and associated motor symptoms in PD, there is increasing interest in the non-central nervous system effects of the disease, specifically the gut dysfunction experienced in many patients’ years earlier… The studies supported by this funding will develop a model within our laboratory that will potentially identify a novel modulator of the gut-brain axis in PD and therefore pave the way for future studies.”
Episode 155: The Evolution of the Parkinson’s Foundation Hospital Care Initiative
Of the one million people living with Parkinson’s disease (PD) in the United States, nearly one-third of them will have a hospital encounter each year. When hospitalized, three out of four people with PD will not receive their medications on time, possibly leading to worsening symptoms, medical emergencies, and a significantly increased length of stay, greatly increasing costs to the medical system overall.
To address this problem, the Parkinson’s Foundation developed key tools and resources for patients and providers as part of our Hospital Care Recommendations. Today’s guest, Peter Pronovost, MD, PhD, a major force in advancing hospital safety, helped develop these recommendations for making hospitals safer for people with PD, which includes standards of care. Dr. Pronovost practices critical care medicine and is Chief Quality Officer and Chief Clinical Transformation Officer at University Hospitals in Cleveland, Ohio.
Released: July 25, 2023
Peter Pronovost, MD, PhD, is a world-renowned patient safety champion, physician executive, critical care physician, prolific researcher with more than 1000 peer-reviewed publications, an innovator who has founded several technology companies, and a thought leader informing U.S. and global health policy.
Dr. Pronovost’s transformative work leveraging checklists to reduce central line-associated bloodstream infections has saved thousands of lives and earned him national acclaim. This life-saving intervention has been implemented across the U.S., and as a result, central line-associated infections that used to kill as many people as breast or prostate cancer have been reduced by 80 percent. In recognition of this innovation, his highest-profile accolades include being named one of the 100 most influential people in the world by Time Magazine and receiving a coveted MacArthur Foundation “genius grant.”
While serving as Chief Clinical Transformation Officer at University Hospitals Health System in Cleveland and as a Professor in the Schools of Medicine, Nursing and Management at Case Western Reserve University, Dr. Pronovost developed a checklist to make visible defects in value and deployed a management and accountability system to eliminate those defects.
This system reduced the annual cost of care for Medicare patients by 30% over three years while improving quality. In 2022, Dr. Pronovost lead the efforts that culminated in University Hospitals winning the American Hospital Association’s Quest for Quality award, the industry’s most prestigious honor recognizing its member organizations for their commitment to quality. He was named the Veale Distinguished Chair in Leadership and Clinical Transformation in 2023.
Studying the Intersection of Movement and Cognitive Disorders to Better Understand Parkinson’s Disease
Chi-Ying Lin, MD, MPH, is researching how movement and non-movement symptoms intersect for people with Parkinson’s disease (PD) and Alzheimer’s disease. Through studying these symptoms in people with movement disorders and cognitive disorders, he hopes to learn more about what parts of the brain produce specific symptoms, which could lead to new treatments for people with Parkinson’s.
Following his Parkinson’s Foundation fellowship at Columbia University Irving Medical Center, Dr. Lin is now an assistant professor of neurology at Baylor College of Medicine with dual appointments in the Alzheimer’s Disease and Memory Disorders Center and the Parkinson’s Disease Center and Movement Disorders Clinic, which is a Parkinson’s Foundation Center of Excellence. We spoke to Dr. Lin to learn more about his work and what he finds most promising in current Parkinson’s research.
What led you to Parkinson’s research?
I was very interested in the personalization of Parkinson’s evaluation and treatment plans, and in learning more about how movement and cognitive symptoms intersect.
I came to the United States after my residency in Taiwan because I was interested in neuropathology at Columbia University. When I arrived, I had a chance to hear Dr. Stanley Fahn speak about movement disorders and it blew me away. I decided I wanted additional training in movement disorders. Because of the excellent clinical training and mentorship opportunities in the U.S., I decided to restart my career here, which led me to my residency at Mount Sinai and my fellowship at Columbia University Irving Medical Center, which was supported by the Parkinson’s Foundation.
Why research the intersection of movement disorders and cognitive disorders?
In my first exposure to cognitive disorders in Taiwan, I was not entirely aware that people with movement disorders actually have a lot of cognitive issues. At Columbia University, I learned through the Parkinson’s Foundation that around 50% of people with PD could have either mild cognitive impairment or dementia. I felt it was important to study this intersection, which is a relatively new field.
There is a brain region called the cerebellum that sits right behind the brainstem and above the neck. It used to be thought of as a pure motor organ and was often studied to understand movement. However, in the past 10 years, there has been an increased understanding that the cerebellum controls non-movement symptoms as well.
Getting To Know the Brain
The cerebellum, which means “little brain,” is primarily responsible for coordination of movement, maintaining posture and balance, muscle tone and motor learning. Recent research also started to reveal the role of cerebellum in non-movement symptoms.
The basal ganglia is an interconnected group of brain structures that control movement, thinking and emotions.
Can you tell us about your impulse control study?
In my fellowship, I conducted studies, and one primarily focused on the intersection of movement and cognitive disorders, especially for impulsivity and compulsivity, which are commonly seen in people with Parkinson’s. This study compared impulsivity in people with Parkinson’s to people with a different cognitive condition, Cerebellar Ataxia, which can include impulsive behavioral symptoms as well.
Our findings determined that impulsivity was different between the two conditions, and with Parkinson’s disease, it can be more widespread to include several impulsive behaviors that are both movement and non-movement related, including gambling, eating, hypersexuality, spending and compulsively taking medication. This suggests that that cerebellum and basal ganglia, a different part of the brain that is affected by PD, can produce different kinds of impulsive behaviors, furthering our understanding of how the cerebellum functions.
What are you currently researching?
The goal of my current study is to better understand the genetic and environmental factors that lead to Alzheimer’s or Parkinson’s in each participant.
I am on dual appointment in the Parkinson’s Center and Alzheimer’s Center. I’m also part of Baylor’s Precision Medicine Core, where I comprehensively study people with and without cognitive disorders and use clinical history, comprehensive assessments, neuroimaging and genome sequencing to characterize early cognitive impairments and determine the risk a person has for a cognitive disorder. Houston, TX, where Baylor is located, is the most racially and ethnically diverse city in the country, which makes it a great place for this study.
Furthering the work I did during my fellowship; I’m also conducting a functional neuroimaging project to identify the role of the cerebellum in both Alzheimer’s and Parkinson’s. Once we understand the role, we can consider treatments like deep brain stimulation to address impulsivity and compulsivity.
What gives you hope for the future of Parkinson’s research?
My overarching goal is to be part of the experts in the world that find the modifying therapy or, to be ambitious, the corrective therapy for Parkinson’s. Practically, I want to address the symptoms of Parkinson’s, which is why I’m focusing on the cerebellum and its impulsivity power to see if we can better address that symptom for people with Parkinson’s.
What do you see as the most promising recent discoveries in Parkinson’s research?
The Parkinson’s Foundation genetics study, PD GENEration, Mapping the Future of Parkinson’s Disease, is something that my patients and their families benefit from immensely because it not only includes genetic testing, but genetic counseling as well at no cost to participants. I’ve enrolled many patients into the study, and I think overall it will be a very fruitful study for Parkinson’s research.
I also believe the Parkinson’s Foundation study about alpha synuclein detection in stool is very interesting and could lead to earlier Parkinson’s disease detection. It interests me because it is noninvasive and could allow for early-stage study recruitment.
How has support from the Parkinson’s Foundation impacted your career?
My fellowship taught me that Parkinson’s does not look the same in every person, and care must be individualized. I’m so appreciative of the support I’ve received from the Parkinson’s Foundation.
There are not enough movement disorders specialists, especially in rural areas, and the Foundation’s support of expanding care for people with Parkinson’s is so important.
Because of the Parkinson’s Foundation, I was able to learn from well-respected movement disorders leaders and build upon my foundation as a movement disorders neurologist. I was lucky to be in the last fellowship class trained by Dr. Fahn before his retirement. He taught me how to be a very compassionate movement disorders neurologist who actively works with patients and their families to find the best treatment options.
A healthy immune system recognizes and fights off illness and disease. Inflammation is part of that process. However, if inflammation persists over long periods of time — which might be the case in Parkinson’s disease (PD) — it can begin to do more harm than good. New research suggests that inflammation may play a critical role when it comes to Parkinson’s.
Studies have shown that inflammation is linked to certain Parkinson’s symptoms and that people with Parkinson’s have markers of inflammation (certain proteins or chemicals that are associated with the inflammatory process) in their blood and cerebrospinal fluid. Moreover, research indicates that manipulating inflammation in an animal model of Parkinson’s resulted in damaging changes in the brain.
Many questions remain about the exact role and mechanisms of inflammation in Parkinson’s. Most importantly, scientists want to untangle whether inflammation plays a role in the onset of Parkinson’s, or whether it is a result of the disease. Another significant question is whether inflammation is associated with certain clinical features that could predict disease progression.
A new study published in Movement Disorders by Talene Yacoubian, MD, PhD, a neurologist at University of Alabama at Birmingham and a Parkinson’s Foundation Scientific Advisory Board member, and colleagues addresses some of these questions. Dr. Yacoubian and her team designed a clinical study to assess the presence of inflammation in those who were within two years of a Parkinson’s diagnosis — before starting medication that may lead to changes in inflammation.
The goal of the study was to determine whether inflammation is present early in Parkinson’s, and whether certain markers of inflammation were correlated to clinical features. The authors plan to follow the study participants to see how inflammation changes in individuals over time.
A total of 120 participants were enrolled in the study. Of those, 58 had Parkinson’s and 62 were healthy controls (did not have PD). Researchers collected blood from all participants to look for various markers of inflammation. A subset of participants also had cerebrospinal fluid samples collected and/or had regions of their brains imaged using a technique that is used for to analyze neuroinflammation.
Study Results
Individuals with Parkinson’s showed significantly higher levels of brain inflammation than people without PD in several brain regions. This measure of brain inflammation was also correlated with other markers of inflammation in the blood and cerebrospinal fluid.
Researchers looked at whether the brain imaging results were correlated with any clinical measure in participants with Parkinson’s. They found that inflammation in several brain regions was associated with worse visuospatial and cognitive scores.
What do these findings mean to the people with PD right now?
Currently, brain inflammation markers cannot be used to diagnose Parkinson’s or predict disease progression. Additionally, we do not yet know whether Parkinson’s medications have any impact on inflammation, nor do we yet know how inflammation changes over the course of the disease.
How are these findings important for the development of future treatments?
Measures of inflammation may help predict cognitive decline. However, we need long-term studies designed to measure inflammatory signals and associated cognitive outcomes to better understand the relationship between these two processes.
Long-term follow-up of study participants will be critical in understanding the significance of early inflammatory signals in Parkinson’s.
There are already multiple studies underway that further delve into inflammation and neurodegeneration. This research can ultimately lead to doctors being able to track inflammation to assess disease progression, and to the development of therapeutics that target inflammatory pathways in Parkinson’s.
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.
In 2016, Karl Heilbron, PhD, joined 23andMe as a postdoctoral researcher studying Parkinson's disease (PD). He knew his work with genetic data could be important to improving the lives of people with PD in the future but wanted to do something to support them now.
“I’m a geneticist by training and basically my job was to try and make some new research discoveries regarding Parkinson’s disease using a large amount of genetic data that 23andMe had collected,” Karl said. “My boss at that time also happened to be living with Parkinson’s. I was inspired by seeing his daily struggles with the disease to do something more to help. I knew that working with these data could hopefully lead to discoveries that could improve the lives of people with Parkinson’s, or even lead to a cure, but that could take time because research is a long road. I wanted to get more involved and actually meet other people with Parkinson’s and find a way to help them today.”
Karl learned about the Parkinson’s Foundation from his boss and decided to start a company team for Moving Day. Now, years later, employees at 23andMe look forward to Moving Day San Francisco every year. However, it's not just the walk they are excited about — it's the company-wide talent show they put on to raise money that keeps people talking.
From musical acts and art displays to “synchronized scientists” portraying genetic code in an elaborate on-land synchronized swimming spectacle, the 23andMe talent show allows employees to share their skills and get to know their coworkers in a new way.
"People tell us every year that this is the company event they look forward to most," said Karl. "For one day, you get to see all of the talents your coworkers have, have a ton of fun and feel great about raising money for an excellent cause."
The 23andMe team has grown each year. In addition to the talent show, they hold a bake sale and silent auction. In 2022, the 23andMe team raised $25,831 and the company's Co-founder and CEO, Anne Wojcicki matched that amount for a total of $51,644.
“It’s a real day of unity and a whirlwind of excitement for the whole company,” Karl said. “Everyone loves the entertainment and sharing their talents, and they also leave the day feeling very good about what they raised money for.”
Karl feels his involvement with the Parkinson’s Foundation, and in getting his coworkers involved, has allowed him to fulfill his desire to help people living with Parkinson’s today. He is excited about the research the Foundation funds but appreciates all of the resources it has developed to assist people living with Parkinson’s, especially community programs.
“I served as a community grant reviewer last year and I got to take a peek behind the scenes of the kinds of programs that receive funding from the Parkinson’s Foundation,” he said. “I could really see the attention the Foundation gives to trying to ensure everyone with Parkinson’s has access to resources, regardless of where they live.”
Karl is proud of all of the funds his Moving Day team has raised for the Foundation and hopes other companies will get creative to raise money and awareness like 23andMe has. He has even developed a “playbook” to help other companies/individuals start their own fundraising team. If you are interested in learning more, feel free to reach out to him.
"Our team has been the number two team in the country for the past few years," Karl said. "That’s something we are really proud of, and we're proud to support everything the Foundation is doing to help people with Parkinson's."
Neuro Talk: 3 Promising Developments in Parkinson’s Research
Every year, the Parkinson’s Foundation funds the most exciting and promising research ideas in the Parkinson’s disease (PD) field. In our latest Neuro Talk, Chief Scientific Officer James Beck, PhD, is joined by three researchers whose studies were funded by the Parkinson’s Foundation. Their projects, which range from investigating environmental factors to understanding cognition, explain how research is helping us further our understanding of Parkinson’s.
Environmental factors that are linked to increased PD risk include pesticides, such as rotenone and paraquat, and the industrial solvent trichloroethylene (TCE). These chemicals disrupt the functioning of the mitochondria, the “powerhouse” of the cell. In addition, Dr. De Miranda has found that rotenone, paraquat and TCE cause activation of the protein affected by one of the most commonly inherited PD genetic mutations, LRRK2.
Dr. Sampson received a Stanley Fahn Junior Faculty Award to understand how Parkinson’s-linked pesticides affect the gut microbiome, the complex community of bacteria and other microbes, in the intestinal tract.
Studies suggest that people with PD harbor distinct gut microbiomes. By identifying gut microbiome changes, the effects of those specific changes on the body, and interactions between environmental exposure and genetic factors, Dr. Sampson hopes to link how insecticides trigger these defects of the intestinal tract and trigger Parkinson’s symptoms.
While therapies are available for some movement symptoms of PD, people with Parkinson’s may also deal with cognitive issues related to memory or attention. Dr. Wilkins is working to determine which PD symptoms are left unaddressed by current approaches, in hopes of developing novel treatments.
Neuro Talk: Strategies for Managing Parkinson’s Disease Symptoms
Each person’s experience with Parkinson’s disease (PD) is unique. Understanding how to manage symptoms can take time, but will ultimately empower you to live better with PD.
In our latest Neuro Talk, Chief Scientific Officer James Beck, PhD, discusses common movement and non-movement symptoms of Parkinson’s. Dr. Beck also explains available treatments and ongoing research related to both types of symptoms.
