IBD and Parkinson’s disease: Study discovers genetic link

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Is there a genetic link between inflammatory bowel disease and Parkinson’s? Aks Huckleberry/500px/Getty Images
  • Previous research has identified associations between Parkinson’s disease and inflammatory bowel disease.
  • A new study examines the genetic link that underpins this relationship.
  • While confirming the role of some well-known genes, the scientists also identify new genes of interest.
  • The authors hope the discovery might help researchers identify better and more effective treatments for both conditions.

A recent study conducted by scientists from the Icahn School of Medicine at Mount Sinai, NY, uncovers fresh details about the links between Parkinson’s disease and inflammatory bowel disease (IBD).

In agreement with previous work, they show that variants of a gene called LRRK2 are important in both conditions. They also identify new genes and pathways that Parkinson’s and IBD share.

The authors hope that uncovering these common biochemical pathways might provide new insights into potential treatments for both conditions.

Parkinson’s is a progressive neurodegenerative condition that affects a region of the brain called the substantia nigra. As it progresses, there is a reduction in dopamine, which produces symptoms that include stiffness and tremors.

IBD, on the other hand, affects the digestive system, causing bloating, stomach cramps, diarrhea, and constipation.

These two conditions appear unrelated on paper — one primarily affects the gut, while the other mostly impacts the brain.

However, experts have long known about links between Parkinson’s and the gut.

Medical News Today spoke with Daniel Truong, MD, a neurologist and medical director of the Truong Neuroscience Institute at MemorialCare Orange Coast Medical Center in Fountain Valley, CA.

Truong, the editor-in-chief of the Journal of Clinical Parkinsonism and Related Disorders, was not involved in the current study.

“In the early 19th century, James Parkinson, after whom the disease is named, noted gastrointestinal symptoms,” he explained. “Constipation is one of the most common non-motor symptoms of Parkinson’s and can often precede the motor symptoms by several years.”

More recently, some research has shown that people with IBD have an increased risk of developing Parkinson’s later in life. Scientists want to understand why.

One of the hallmarks of Parkinson’s are so-called Lewy bodies in the brain. These are mostly formed of a protein called alpha-synuclein.

This protein buildup is a tell-tale sign of Parkinson’s, but it is unclear whether Lewy bodies themselves are toxic or the buildup is part of the body’s defense mechanisms.

Either way, some evidence suggests that these misfolded proteins may start their life in the gut in response to long-term inflammation and eventually move to the brain.

“The presence of alpha-synuclein in the gut’s nervous system supports the hypothesis that Parkinson’s pathology might start in the gut and spread to the brain via the vagus nerve,” Truong explained to MNT.

Beyond protein buildup, previous research has also noted associations between alterations in a gene called LRRK2 and both IBD and Parkinson’s.

To date, LRRK2 is the most well-established genetic link between the two conditions. It seems that different variants of this gene can either increase or decrease the risk of both diseases.

In the latest study published in Genome Medicine, researchers examined rare genetic variants to unpick the connections between LRRK2, IBD, and Parkinson’s.

The researchers analyzed genetic data from the BioMe BioBank and UK Biobank and whole genomes from 67 people with both IBD and Parkinson’s.

Following analysis, the authors confirmed that certain variants of LRRK2 are associated with an increased risk of Parkinson’s and IBD. They also found other gene variants that might play a role.

MNT spoke with one of the study’s authors, Meltem Ece Kars, MD, Ph.D., from The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai.

She was surprised that “although there was a minimal overlap between the IBD-Parkinson’s-associated genes and previously known Parkinson’s and IBD genes, pathway enrichment analyses showed prominent overlaps in these three conditions.”

In other words, the genes that these two conditions share are different from those that cause Parkinson’s and IBD, individually. However, they appear to influence similar biochemical pathways.

“Interestingly,” she continued, “we also detected significantly enriched pathways unique to IBD-Parkinson’s, such as MAPK signaling, LPS/IL-1 mediated inhibition of RXR function, and NAD signaling.”

These pathways might be important because, as the authors write, they have “established or suggested roles in intestinal inflammation and neuronal metabolism.”

We asked Kars what the LRRK2 gene does in healthy individuals.

She told us it “plays a role in transporting biochemical molecules between cells and maintaining cell components, as well as phagocytosis and autophagy, which are physiological processes to remove foreign, dysfunctional, and unnecessary substances from cells.”

Importantly, she told us that “it has also been shown to play an important role in the regulation of inflammation and immune processes.”

Inflammation is pivotal in Parkinson’s disease, Truong told MNT.

“Neuroinflammation, characterized by the activation of glial cells — immune cells of the central nervous system — is a hallmark of Parkinson’s,” he added.

We asked Kars how these results might guide the search for new treatments for both conditions:

“We identified 14 genes, including LRRK2, as potential candidates for further validation in clinical settings for future targeted therapies. Additionally, the pathways related to inflammation and autophagy identified in this study can pave the way for developing novel therapeutic strategies and drug repurposing.”

MNT asked Kars whether they would be continuing this line of investigation:

“Given the shared mechanisms underlying IBD and Parkinson’s, we would want to test whether medications used for one of these conditions could apply to another leading to drug repurposing.”

“We already showed that LRRK2 inhibitors, developed to treat Parkinson’s, eased experimental colitis [a form of IBD] in a mouse model,” she continued, “indicating that these drugs could help open novel therapeutic avenues for patients with IBD.”

Along these lines, previous studies have shown that treatment with anti-TNF therapy — a common treatment for IBD — reduces the risk of developing Parkinson’s.

According to Kars, this suggests that “reducing peripheral inflammation could be a prudent way to prevent Parkinson’s. Optimizing these drugs and testing them in clinical trials would be an important next step.”

Truong agrees, “Research is ongoing into the use of non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and other anti-inflammatory agents to slow Parkinson’s progression.”

Also, as the researchers identified, “the involvement of genes related to immunity, inflammation, and autophagy suggests that drugs modulating these processes could be effective.”

“For instance,” Truong continues, “anti-inflammatory drugs or autophagy enhancers could be explored for their efficacy in both IBD and Parkinson’s.”

Although scientists have much more work to do, developing a deeper understanding of how IBD and Parkinson’s work is an important next step along the path to better treatments for both.

Read the full article here

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