From Gut Instincts to Research Breakthroughs: How the University of Florida Connected Alpha-synuclein, Inflammatory Bowel Disease and Parkinson’s

In a landmark investment to accelerate the path to a Parkinson’s disease (PD) cure, in 2019, the Parkinson’s Foundation awarded $8 million to establish four elite Parkinson’s Foundation Research Centers: Yale School of Medicine, University of Michigan, University of Florida and Columbia University. Each one received $2 million over four years.

In this series of articles, we share each center’s story — their goals, successes, surprises and the future of their PD research. In this article, we cover the research progress made at the Parkinson’s Foundation Research Center and Center of Excellence at the University of Florida.

Exploring the Overlaps Between IBD and PD

Since the first classification of Parkinson’s disease (PD) over 200 years ago, gastrointestinal distress has been routinely linked to PD. As many as 80% of people with PD experience digestive non-movement symptoms such as constipation, nausea and gastroparesis (delayed emptying of the stomach). 

More severe inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, are linked to an increased risk of developing PD. Scientists are working to solve why the diseases are linked and how improving gut health could have protective effects against PD development and progression.

Researchers at the University of Florida, along with collaborators at Emory University, investigated three distinct yet connected elements of gut health and PD:

• Malú Gámez Tansey, PhD, and Parkinson’s Foundation Scientific Advisory Board member, uncovered how genetic variants of LRRK2 that are associated with PD impact inflammation in the gut and how that affects the brain. 
• Tim Sampson, PhD, discovered how alpha-synuclein, the hallmark protein in PD, plays an important role in protecting the gut from infection. 
• Nikloaus McFarland, MD, PhD, Chris Forsmark, MD, and Michael Okun, MD, Parkinson’s Foundation National Medical Advisor, collaborated with Dr. Tansey to find common gut health “molecular signatures” between people with PD and IBD.

LRRK2 Variants Lead to Immune System Burnout in the Gut and Brain

Genetic variants in the LRRK2 gene significantly increase the risk for developing PD, particularly when combined with other risk factors. PD GENEration, the international research study that provides genetic testing and counseling at no cost for people with PD, determined that 12% of study participants had a primary PD gene variant. Of those, 17% had a PD-associated LRRK2 variant.

LRRK2 variants are also associated with increased risk of developing Crohn’s disease, a chronic inflammatory bowel disease. Dr. Tansey, who has researched PD for more than 20 years, theorized that this LRRK2 overlap between Crohn’s disease and PD highlights how gut inflammation could lead to neurodegeneration in the brain.

“Before this award, investigations into LRRK2 and alpha-synuclein and any interaction between them was mostly focused on the brain, not the gut.”

– Dr. Tansey

First, Dr. Tansey and her team induced colitis — inflammation in the large intestine — in mice and observed how it impacted their gut and brain health. They found that colitis triggered immune system responses in the gut and the brain and altered the types and amounts of protein produced in the brain during peak inflammation. These findings strengthen evidence for the gut-brain axis, showing how inflammation in the gut can affect brain health.

Dr. Tansey then investigated how a PD-associated LRRK2 variant, called R1441C, affected mice. Interestingly, young mice with a R1441C had stronger, more reactive immune systems driven by increased effectiveness of an immune cell type called macrophages. However, this exhausted their immune system in the long run, reducing their ability to fight infection and manage inflammation. The researchers confirmed that these effects were directly linked to LRRK2 activity.

These studies highlight two scientific takeaways: 

1. Inflammation in the gut triggers immune system reactions in the brain.
2. PD-related LRRK2 mutations may weaken the immune system with age, making the brain more vulnerable to infection and inflammation. 

With ongoing and future experiments, Dr. Tansey wants to connect these dots by examining how the brain reacts to chronic gut inflammation and different LRRK2 genetic variants. Such research will significantly advance our understanding of how PD and Crohn’s disease are interconnected and how effectively treating one could positively impact the other.

Alpha-Synuclein Protects the Gut from Bacterial Infection, But Too Much Could Endanger the Brain

In PD, alpha-synuclein proteins misfold and form disruptive clusters in the brain called Lewy bodies. These clumps may trigger the loss of dopamine-producing neurons. Scientists have also found misfolded alpha-synuclein in the gastrointestinal (GI) tract in people with PD. But alpha-synuclein may also play an important role in protecting the GI tract.

Dr. Sampson, an Emory University co-investigator for the PF Research Center, sought to understand alpha-synuclein’s positive role in gut health. This research could help explain how alpha-synuclein can become disrupted in ways that then contribute to PD. He and his team first wanted to determine if alpha-synuclein protects against bacterial infection in the gut. 

“Since others have observed that alpha-synuclein is important for controlling infections and that certain microbes (bacteria, viruses) can result in its upregulation, we were interested in understanding what its contribution to immunity may be.” 

- Dr. Sampson. 

They used three types of mice: one with no alpha-synuclein, another with extra alpha-synuclein, and one with a normal amount of alpha-synuclein. Dr. Sampson observed how the mice reacted to a C. rodentium infection, a bacterium that affects mice like E. coli affects humans.

The mice without alpha-synuclein had a significantly worse time dealing with the infection compared to the normal mice, while the mice with extra alpha-synuclein showed stronger immune resistance to the bacteria. 

These results support the hypothesis that alpha-synuclein has a protective immune role in the gut, and future experiments are being designed to uncover how it works. Early data suggest that alpha-synuclein might act directly on the bacterial populations in the gut, curating a gut environment that resists infection from foreign microbes.

Despite these benefits, Dr. Sampson and his team suspected that alpha-synuclein could also harm the brain and nervous system. To test this, after the mice recovered from the infection, the researchers examined neurons in the gut and brain and found a loss of dopamine neurons in both areas. The extra alpha-synuclein also appeared to form Lewy body-like clumps. 

These experiments have uncovered new information about alpha-synuclein and its importance in the gut-brain axis. Dr. Sampson’s current research is exploring how alpha-synuclein protects the gut and how future therapies could preserve these benefits while preventing its role in PD development.

PD and IBD Share Key “Molecular Signatures” In the Microbiome

With PD and IBD being closely linked, understanding their shared biology could identify new treatments that protect gut health and lower PD risk. This was the rationale behind the third research center project, led by Dr. Tansey with collaborations from Drs. McFarland, Forsmark and Okun. 

“The long-term goal of these studies was to understand the extent to which having IBD may increase the risk for PD in certain individuals, and the extent to which a therapeutic intervention that helps patients with IBD could also help patients with PD.” 

– Dr. Tansey

In this study, the research team sought to find similarities and differences between people with PD and IBD in their gut microbiomes. The microbiome is a complex ecosystem of trillions of bacteria, fungi, viruses and other microorganisms that live in a person’s digestive system. Maintaining a healthy microbiome is important for digestion, immunity and brain health — while microbiome disruption can lead to health issues.

Dr. Tansey and her colleagues recruited 54 people with PD, 24 with IBD, and 16 without either disease to provide fecal, blood and gut tissue samples that offer a snapshot of their microbiomes and immune systems. Using special microbe-measuring techniques, they created microbiome maps for each group and compared them. 

Their key finding was that people with both PD and IBD had lower levels of bacteria that produce short-chain fatty acids, which help control inflammation and protect the brain. 

While it is unclear whether these changes cause or result from PD or IBD, reduced amounts of short-chain fatty acids may be important treatment targets for both diseases. Future research will explore how these microbiome trends work and can help prevent IBD and PD. 

“Thinking Outside the Box by Looking Outside the Brain”

Charting the connections between IBD and PD along the gut-brain axis is no simple feat. Thanks to support from becoming a Parkinson’s Foundation Research Center, the University of Florida and Emory University research teams made significant scientific progress toward understanding how these diseases overlap.

These projects also fostered new academic collaborations that are accelerating PD research into the future. “Being a Research Center promoted multidisciplinary team science between Emory neuroscientists and University of Florida neuroscientists and neurologists,” said Dr. Tansey, “It helped us sharpen our focus and next steps to collaborate with gastroenterologist Rodger Liddle at Duke to receive a larger extramural grant from the ASAP Collaborative Research Network on the gut-brain circuit in Parkinson’s.”

Each project’s success has also empowered new research directions for the others; for example, the human microbiome research uncovered new biological pathways that can be further explored using mice. “Through the UF team's interrogation of human PD, we now have highly relevant pathways to test in animal models and correlate back to humans,” said Dr. Sampson. “These projects are still ongoing, and we are excited to continue our collaborations that were initiated through the Center.”

These breakthroughs have also accelerated the scientific careers of new PD researchers. Rebecca Wallings, PhD, assisted Dr. Tansey with the research into how LRRK2 variants affect the immune system. During this work, Dr. Wallings wanted to learn more about how innate immune cells were impacted, so she applied for and received a Parkinson’s Foundation Launch Award to do so. This continued support has helped Dr. Wallings get to where she is now: running her own lab focused on LRRK2 PD research. 

From uncovering the important gut immunity roles for two PD-related proteins — LRRK2 and alpha-synuclein — to identifying microbiome similarities between those with PD and IBD, these experiments led to foundational scientific breakthroughs. 

“Thanks to Parkinson’s Foundation support, we became committed to more focused investigations into the role of LRRK2-synuclein interactions in the gut-brain axis. It has also cemented our interest in continuing 'to think outside the box by looking outside the brain' for earlier manifestations of PD pathogenesis,” said Dr. Tansey. 

These research discoveries, and many more to follow, will continue to advance new treatments for PD and IBD, building on the Parkinson’s Foundation commitment to research.

Today, Dr. Tansey is the professor of neurology and the James A. Caplin, MD, Chair in Alzheimer’s Disease at the Indiana University School of Medicine. Rebecca Wallings is also at the Indiana University as an assistant professor and principal investigator of the Wallings Lab. 

Learn More

The Parkinson’s Foundation works to improve care for people with PD and advance research toward a cure. Learn more with these resources:

• Read the first two articles in this series: 
  • From Parkinson’s Foundation Research Center to Powerhouse: How Yale Became a Leader in Parkinson’s Science
  • Mapping the Brain in High Resolution: How the University of Michigan is Advancing Parkinson’s Neuroscience
• Discover how we are working to close gaps in knowledge about PD: Advancing Research.
• Learn about and enroll in PD GENEration — a global genetics study that provides genetic testing and counseling at no cost for people with Parkinson’s.
• Explore ways to get involved in the Parkinson’s Foundation — from becoming a research advocate to joining a research study.