Link established between Parkinson's-associated protein and upper GI infection

By Liz Meszaros, MDLinx
Published June 30, 2017

Key Takeaways

Frequent and chronic upper gastrointestinal infections may overthrow the body’s capability of clearing alpha-synuclein (αS), a protein that has been implicated in Parkinson’s disease and other neurodegenerative diseases, according to scientists at Georgetown University Medical Center, Washington, DC, and collaborators at the National Institutes of Health. They published their findings in the Journal of Innate Immunity.

Alpha-synuclein is abundant in the brain, although its function is currently unknown. It is also a major component of Lewy bodies, the protein clumps that are the pathological hallmark of Parkinson's disease.

Previous research has shown that αS build-up begins in the enteric nervous system in patients with very early and later stages of Parkinson’s. Animal studies have also shown that microbes in the GI tract may induce the formation of toxic aggregates in the enteric nervous system, which may travel to the brain.

Patients with Parkinson’s disease often have chronic constipation due to enteric nervous system damage that can develop decades before neurologic symptoms are apparent. These patients often also have chronic upper GI distress once Parkinson’s disease develops.

In this study, researchers immunostained endoscopic biopsies for αS from 42 children who had documented gastric and duodenal inflammation, as well as from 14 intestinal allograft recipients with norovirus. They found that expression of αS in enteric neurites of the upper GI tract in these children was positively correlated with the degree of acute and chronic inflammation they had in the intestinal wall. In the intestinal allograft patients, αS expression was induced during norovirus infection.

Researchers also demonstrated that human αS was a potent attractor of human immune cells, including macrophages and neutrophils, and could ‘turn on’ dendritic cells to alert the immune system.

“When expressed in normal amounts following an infection of the upper GI tract, αS is a good molecule.  It is protective,” explained senior investigator Michael Zasloff, MD, PhD, professor of surgery and pediatrics at Georgetown University School of Medicine, and scientific director, MedStar Georgetown Transplant Institute. “The nervous system within the wall of the GI tract detects the presence of a pathogen and responds by releasing αS. αS then attracts white blood cells to the site where it has been released. In addition, αS produced in one nerve can spread to others with which it communicates thereby protecting a large field. By this means, the nervous system can protect both itself as well as the GI tract as a whole in the setting of an infection.”

Dr. Zasloff and colleagues noted that their findings strongly suggest the expression of αS in the human enteric nervous system in the presence of intestinal inflammation, and may implicate common GI infections in the pathogenesis of Parkinson’s disease.

“It is well known from animal studies that αS produced in the enteric nervous system can use the nerves connecting the GI tract to the brainstem as an escalator, trafficking αS from the gut to the brain and spreading to centers within the central nervous system,” said Dr. Zasloff. “But too much αS—such as from multiple or chronic infections—becomes toxic because the system that disposes of αS is overwhelmed, nerves are damaged by the toxic aggregates that form and chronic inflammation ensues. Damage occurs both within the nervous system of the GI tract and the brain.”

Previous work from Dr. Zasloff and colleagues showed that squalamine reduced the formation of toxic αS clumps in animal trials. He noted that a new phase 1/2 clinical trial has just begun to study the accumulation of αS in the enteric nervous system, and the safety, pharmacokinetics, and pharmacodynamics of ENT-01, a synthetic version of squalamine to relieve constipation association with Parkinson’s disease.

This study was funded by the Intramural Research Program of the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (ZIADK029047), the University of Oklahoma, and UCLA training grants from the National Institute of General Medical Sciences (T32GM008185, T32GM008042). 

The newly initiated phase 1/2 clinical trial is being sponsored by Enterin Inc. Dr. Zasloff is founder, chairman, and CEO of Enterin, Inc.

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