The hallmark brain damage in Parkinson’s disease is thought to be the work of a misfolded, rogue protein that spreads from brain cell to brain cell like an infection. Now, researchers have found that the normal form of the protein—α-synuclein (αS)—may actually defend the intestines against invaders by marshaling key immune cells. But chronic intestinal infections could ultimately cause Parkinson’s, the scientists suggest, if αS migrates from overloaded nerves in the gut wall to the brain.
“The gut-brain immune axis seems to be on a cusp of an explosion of new insights, and this work offers an exceptionally exciting new hypothesis,” says Charles Bevins, an expert in intestinal immunity at the University of California, Davis, who was not involved with the study.
The normal function of αS has long been a mystery. Though the protein is known to accumulate in toxic clumps in the brain and the nerves of the gut wall in patients with Parkinson’s disease, no one was sure what it did in healthy people. Noting that a region of the αS molecule behaves similarly to small, microbe-targeting proteins that are part of the body’s immune defenses, Michael Zasloff, an immunologist at Georgetown University Medical Center in Washington, D.C., set out to find whether αS, too, might help fend off microbial invaders.
To see whether αS was indeed playing a role in the gut’s immune defenses, Zasloff, Ethan Stolzenberg of the University of Oklahoma Health Sciences Center in Oklahoma City, and their colleagues spent 9 years collecting and analyzing biopsies of the duodenum—the first part of the intestine where nerves normally produce very little αS—from 42 children unlikely to have Parkinson’s disease. (The early stages of the disease virtually never appear until adulthood.) The children had abdominal pain, diarrhea, vomiting, and other gastrointestinal symptoms, along with gut inflammation visible under a microscope. The scientists found that the αS protein was indeed present in the nerves of the inflamed intestine—and the more intensely inflamed the tissue was, the more αS the team found.
But was the αS a cause or an effect of the inflammation? To find out, the researchers turned to biopsies from 14 children and two adults who received intestinal transplants and later developed infections with norovirus, a common gut pathogen. In most, the αS protein was abundantly evident during infection. In four of nine patients—whose intestines had been biopsied before, during, and after the infection—the αS protein appeared only during the infection, but not before. (Zasloff conjectures that the five patients who showed αS production prior to infection were making it in response to another, pre-existing viral infection.)
Next, the scientists asked whether the αS protein was acting as a magnet for inflammatory cells, which are a key part of a normal immune response. In lab dish experiments, they found that αS, whether in its normal conformation or in the misfolded aggregates found in Parkinson’s disease, powerfully attracted white blood cells that are present in both acute and chronic inflammation. They also discovered that both forms of αS activated dendritic cells, which lead to lasting immunity by presenting bits of foreign invaders to lymphocytes—the white blood cells that “remember” specific microbial intruders and respond in force to later invasions. After exposing immature dendritic cells to αS for 48 hours, the team discovered that the more αS, the more dendritic cells were activated. Together, the data suggest the production of αS by nerves in the gut wall is the cause—and not the effect—of tissue inflammation, the authors write today in the Journal of Innate Immunity. “This discovery shows us that the [gut’s] nervous system can play a key role in both health and disease,” Zasloff says.
The authors note that people with multiple copies of the gene that directs the production of αS inevitably develop Parkinson’s disease—in essence, production of the protein overwhelms the body’s ability to clear it, and it forms the toxic aggregates that cause Parkinson’s. They also write that repeated acute or chronic gut infections could produce “a comparable increase” in αS.
The paper’s findings are “thrilling,” says Aletta Kraneveld, an immunopharmacologist who studies the gut-brain axis at the University of Utrecht in the Netherlands. “This is the first [study] showing that a protein very, very relevant for Parkinson’s disease is able to induce an immune response. It opens up so many avenues for new research.”
Zasloff himself is moving into the clinic, treating Parkinson’s patients for constipation using a synthetic version of squalamine, a natural steroid made by the dogfish shark. Squalamine, says Zasloff, prompts bowel movement and blocks αS action in gut wall nerves. The early phase trial is being conducted by Enterin, a Philadelphia, Pennsylvania–based firm Zasloff founded with his co-author, neurologist Denise Barbut, now Enterin’s chief medical officer. If the drug succeeds in reversing constipation, the researchers will conclude that it has disrupted the function of αS in the intestinal nerves. “This type of approach could also in principle alter the whole natural history of the disease,” Zasloff says.
But David Beckham, a neurovirologist and physician at the University of Denver, is cautious. “Potentially αS is playing some role in helping neurons fight off infections,” he says. But he adds that the current study doesn’t do enough to show that it is a cause and not an effect of inflammation.
“This is an early part of a new emerging understanding of what this molecule potentially does,” Beckham says. “And I think it’s eventually going to lead us in the correct direction as to what’s going wrong in Parkinson’s disease—and potentially to how can we prevent it.”