Even a healthy appendix harbors a clumped form of the protein α-synuclein (red)—a key feature of Parkinson’s disease in the brain.

B. A. Killinger et al. Science Translational Medicine (2018)

Seeds of Parkinson’s disease may hide in the appendix

The appendix has a reputation of being useless at best. We tend to ignore this pinkie-size pouch dangling off our large intestine unless it gets inflamed and needs cutting out. But a new study suggests this enigmatic organ in the gut harbors a supply of a brain-damaging protein involved in Parkinson’s disease—even in healthy people. The study is the largest yet to find that an appendectomy early in life can decrease a person’s risk of Parkinson’s or delay its onset.

“It plays into this whole booming field of whether Parkinson’s possibly starts in the gut,” says Per Borghammer, a neuroscientist at Aarhus University in Denmark who was not involved in the study. “And that would be a radical change in our understanding of the disease.”

Look inside the brain of a person with Parkinson’s and you’ll find clumps of a misfolded form of a protein known as α-synuclein (αS). The protein’s normal function isn’t fully clear, but in this clumpy state, it may damage and kill neurons, including those near the base of the brain that help control movement. The results are the hallmark tremors and body rigidity of Parkinson’s.

But gastrointestinal symptoms—especially constipation—are also common in Parkinson’s patients, and can appear decades before other problems. Scientists have found that people are less likely to get Parkinson’s if they’ve had a vagotomy, a treatment for stomach ulcers that severs the vagal nerve, which branches down from the brain into various tissues of the gut.

That finding feeds a still-controversial theory, proposed more than a decade ago by neuroscientist Heiko Braak, that the seeds of Parkinson’s disease somehow climb up out of the gut and into the brain. “It’s kind of like the telephone game,” explains John Woulfe, a neuropathologist at the Ottawa Hospital Research Institute. Dysfunctional αS spreads up the fibers of the vagal nerve, the theory goes, by converting healthy forms of the protein to misfolded, clumpy ones.

In the new study, neuroscientist Viviane Labrie and her team at the Van Andel Institute in Grand Rapids, Michigan, decided to zero in on the appendix. Though it’s not necessary for life, it may not be completely useless; the organ holds immune cells that may help coordinate the gut’s response to pathogens, and bacteria that may help maintain a healthy balance of gut microbes. (Inflammation and microbiome disturbances are both proposed factors in Parkinson’s risk.)

Four recently published studies looked for evidence that people who get appendectomies are less likely to get Parkinson’s; three couldn’t find it, but Labrie’s team did. “This study accomplishes what those studies lacked,” Woulfe says—a large group of people tracked over a sufficiently long time. It relies on a national registry that has logged medical records for 1.7 million Swedish citizens since 1964. There is roughly a 1% chance that a person will develop Parkinson’s after age 65, but for the Swedes who had an appendectomy, the risk of developing the disease was about 20% lower than for those who kept their appendix, the researchers report today in Science Translational Medicine.

“The magnitude [of the effect] is remarkable,” says Michael Zasloff, an immunologist at Georgetown University Medical Center in Washington, D.C., and CEO of a company called Enterin that is testing a potential Parkinson’s drug meant to prevent αS from building up in intestinal nerve cells.

When researchers broke the Swedish population into rural and urban dwellers, however, the benefit of appendectomy only held for the rural group. That’s a clue, Labrie says, that an appendectomy might be most protective in Parkinson’s cases that have some environmental trigger. (Pesticide exposure is a possible candidate.)

To confirm that protective effect, the team analyzed more detailed disease records from an international study of 800 people with Parkinson’s. They found that for those who got an appendectomy 20 years or more before their diagnosis, the onset of Parkinson’s was delayed, on average, by 3.6 years. “When we get rid of [the appendix], you are safe for a few years, but then it just starts somewhere else in the gut,” Borghammer suggests. But if an appendectomy happened later in life, closer to the Parkinson’s diagnosis, the disease’s time of onset was not delayed much beyond the average. An appendectomy also didn’t protect people with one of several inherited genetic mutations strongly linked to Parkinson’s.

Labrie’s team then analyzed appendix samples for different forms of αS. Of 48 samples from healthy people, all but two contained a clumped form of αS similar to that seen in the Parkinson’s brain. That prevalence came as a shock. “It’s present in all of us,” Labrie says, but it only seems to cause trouble if it sneaks up to the brain.

And the appendix may be an important breeding ground for clump-prone αS. When the researchers exposed normal αS to the contents of healthy appendix tissue cells in a dish, the proteins were cleaved into a shorter form, which is more prone to aggregate, and possibly better able to spread to the brain.

As to why most people won’t get Parkinson’s despite having clumpy αS in their appendix, Labrie’s team can only speculate. The team did find a distinctive feature of the appendix of a person with Parkinson’s: It appeared to have about fourfold higher levels of a shortened, clump-prone form of αS than a healthy person’s appendix—though it’s not yet clear that this difference contributed to the development of disease. Maybe some people are inherently better able to manage clumped αS and keep it sequestered away from the brain, the researchers suggest. Or maybe some insult—an infection or a change in the population of gut bacteria—prompts the appendix to make more αS, possibly as a means of recruiting more immune cells and protecting the gut.

Given all the uncertainty, Labrie isn’t suggesting anyone have their appendix taken out to avoid Parkinson’s. “Preventive surgery is too far,” she says. But she hopes future Parkinson’s treatments might control how αS is cut and processed in the body, and thus how it accumulates. In the meantime, her team is now searching for other differences between the appendix of a healthy person and a person with Parkinson’s to explain how and when its resident protein might go rogue.