A recent study has discovered a link between frequent or chronic occurrences of gastrointestinal (GI) tract infections and the development of Parkinson’s disease (PD).
The study’s authors have shown for the first time that the nerve cell protein alpha-synuclein (αS), produced by the enteric nervous system, is a key mediator of intestinal inflammation. The enteric nervous system (ENS) is a network of neurons that independently governs the function of the GI tract. An excessive immune response, which occurs in multiple or chronic infections, may damage enteric neurons and lead to the onset of Parkinson’s.
The study, “A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity,” was published in the Journal of Innate Immunity.
Previous studies claim that αS begins accumulating in the ENS and then travels from the gut to the brain, where it linked to the development and progression of PD. However, until now, αS had no known function in humans, and the reason for its accumulation within the ENS remains unknown.
Through analysis of biopsy samples from GI distressed patients, the researchers found that αS is produced and released by nerve cells in response to an infection in the GI tract, triggering the immune system to generate a response.
Biopsy samples for this study were obtained over a nine-year period from 42 children with GI distress or with the pathological diagnoses of duodenitis, gastritis, Helicobacter pylori infection, or reactive gastropathy. A second group was included to incorporate intestinal transplant recipients who developed a norovirus infection (14 children and two adults).
“When expressed in normal amounts following an infection of the upper GI tract, αS is a good molecule. It is protective. 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,” Michael Zasloff, MD, PhD, senior author of the study, said in a press release. “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.”
According to researchers, these findings suggest that frequent or chronic GI infections could overwhelm the body’s capacity to clear αS, ultimately damaging the central nervous system where it travels and causing PD.
“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 Zasloff, who is founder, chairman, and CEO of the pharmaceutical company Enterin. “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.”
This information coincides with observations of PD patients, who experience chronic constipation due to damage of the ENS, which develops decades before brain symptoms become apparent. Chronic GI distress also is relatively common in people with PD.
Enterin currently is sponsoring an ongoing Phase 1/2a trial, called RASMET (NCT03047629), designed to test its ENT-01 therapy as a means to target the accumulation of αS in the enteric nervous system and relieve Parkinson’s-associated constipation.