Parkinson’s disease proteins linked to upper GI infections
Alpha-Synuclein, a nerve cell protein linked to Parkinson’s disease and other neurogenerative diseases, appears to induce an immune response in patients with upper GI infection, according to a new observational study.
The findings suggest that frequent or chronic upper GI infections could impair the body’s ability to clear alpha-Synuclein that accumulates in the enteric nervous system, which is then trafficked from the gut to the brain, and could thus contribute to the pathogenesis and progression of Parkinson’s disease, according to study investigators.
“When expressed in normal amounts following an infection of the upper GI tract, alpha-Synuclein is a good molecule. It is protective,” Michael Zasloff, MD, PhD, professor of surgery and pediatrics at Georgetown University School of Medicine and scientific director of the MedStar Georgetown Transplant Institute, said in a press release. However, too much alpha-Synuclein resulting from frequent or chronic upper GI infections “becomes toxic because the system that disposes of alpha-Synuclein is overwhelmed, nerves are damaged by the toxic aggregates that form and chronic inflammation ensues,” he added. “Damage occurs both within the nervous system of the GI tract and the brain.”
To clarify the function of this poorly understood protein, Zasloff and colleagues collaborated with the NIH to evaluate biopsy samples from 42 children with upper GI distress obtained over a 9-year period at the University of Oklahoma Health Sciences Center.
These biopsies showed that alpha-Synuclein expression in the enteric nerves of the upper GI tract correlated with the level of acute and chronic inflammation in the intestinal wall.
Further, the researchers evaluated 14 intestinal transplant patients at MedStar Georgetown University Hospital, who had documented norovirus infections. They found that several transplant patients who were highly monitored for infection showed alpha-Synuclein expression as they were infected by norovirus.
The investigators also found that alpha-Synuclein attracted immune cells like macrophages and neutrophils, and activated dendritic cells to induce an immune response to the specific pathogen.
“The nervous system within the wall of the GI tract detects the presence of a pathogen and responds by releasing alpha-Synuclein. Alpha-Synuclein then attracts white blood cells to the site where it has been released,” Zasloff said in the press release. “In addition, alpha-Synuclein 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.”
The researchers concluded that their findings “strongly suggest that [alpha-Synuclein] is expressed within the human [enteric nervous system] to direct intestinal inflammation and implicates common GI infections in the pathogenesis of [Parkinson’s disease].”
Zasloff’s work adds to previous studies of autopsied material from people with both early- and late-stage Parkinson’s, which showed that alpha-Synuclein buildup starts in the enteric nervous system. Additionally, prior animal studies have demonstrated “that alpha-Synuclein produced in the enteric nervous system can use the nerves connecting the GI tract to the brainstem as an escalator, trafficking alpha-Synuclein from the gut to the brain and spreading to centers within the central nervous system,” he said in the press release.
He added that this study “make[s] sense” of GI-related observations in Parkinson’s patients, like chronic upper GI distress, which is relatively common in these patients, and chronic constipation resulting from enteric nervous system damage that occurs decades before brain symptoms emerge.
Zasloff and colleagues have initiated a phase 1/2a clinical trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ENT-01 (Enterin) for relieving Parkinson’s-associated constipation. The study drug is an oral synthetic version of squalamine, a natural steroid made by the dogfish shark, which Zasloff and colleagues have shown in animal models reduces toxic alpha-Synuclein clump formation and toxicity. – by Adam Leitenberger
Disclosures: Zasloff reports he is the founder, chairman and CEO of Enterin, and another researcher (Barbut) is co-founder of Enterin, president and chief medical officer of the company.