Neurons of the appendix contain alpha-synuclein (red), a protein that is also found in the brains of people with Parkinson’s disease.

A squishy, 4-inch gut organ whose function has baffled anatomists for centuries is about to have its moment of fame: The lowly appendix, scientists reported in a study on Wednesday, can initiate Parkinson’s disease.

It does so, they suspect, by serving as a reservoir of misfolded, clumping, neurotoxic proteins that travel to the brainstem via the vagus nerve, which runs from the gut all the way up to the brain. People who had their appendix removed have an almost 20 percent lower risk of Parkinson’s, according to the study in Science Translational Medicine, or a risk of 1.6 per 10,000 people over a decade compared to 1.98 in the general population.

The discovery that appendectomy might reduce but doesn’t eliminate the risk of Parkinson’s shows there are other causes of the disease, a usually-crippling brain disorder that strikes about 60,000 people in the U.S. every year. In addition, appendectomy reduced the risk only in people living in rural areas, not urban ones; not among those who inherited any of three common Parkinson’s-causing mutations, which account for about 10 percent of cases; and only if the surgery occurred early in life, well before Parkinson’s started.

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Rather than weakening the study, however, those qualifications might actually support its explanation of how the appendix (which is attached to the large intestine) can trigger Parkinson’s. That explanation is based on appendectomy data as well as molecular evidence, in particular that the appendixes of Parkinson’s patients contain clumps of a protein called alpha-synuclein very similar to those in Parkinson’s-affected brains.

“It’s a really nice study, and all of their ideas are biologically plausible,” said James Beck, chief scientific officer of the Parkinson’s Foundation, which was not involved in the research. “It connects the epidemiology, about appendectomy reducing the risk of Parkinson’s, with the basic science.”

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Although the appendix is often described as useless or vestigial, it plays a role in the immune system, including by affecting the composition of the gut microbiome and detecting and removing pathogens.

The findings do not mean that everyone worried about Parkinson’s should have an appendectomy, cautioned the study’s senior author, Viviane Labrie of the Van Andel Research Institute in Grand Rapids, Mich. Nor does it mean that everyone with an appendix is likely to develop the disease. It is “a” site of origin for the disease, she said, “but it likely has many sites of origin, including the brain.”

The research does, however, suggest new, appendix-centered approaches to preventing or treating Parkinson’s, which destroys dopamine-making cells in the brain’s substantia nigra. Today’s drugs can replace the lost dopamine but not the destroyed neurons, so although they partly (and temporarily) alleviate symptoms such as tremor and stiffness, they do nothing to stop disease progression.

The new study marshals two lines of evidence for an appendix-Parkinson’s connection, which started off as what Beck calls “a weird idea” in 2003.

The first evidence comes from large databases. One, with medical and demographic information on 1.6 million Swedes going back to 1964, showed that people who’d had an appendectomy were 19.3 percent less likely to develop Parkinson’s. When the scientists analyzed urban and rural residents separately, however, they found no such protective effect in the former. Another data set, of 849 Parkinson’s patients, showed that in those who had an appendectomy, the disease appeared an average of 3.6 years later than in patients who still had their appendix — but again, only for rural residents.

The second line of evidence comes from scrutiny of dozens of appendixes. Parkinson’s patients’ had clumps of alpha-synuclein virtually identical to those in Parkinson’s brains. So did healthy people, but Parkinson’s patients had 4.5 times as much of the short form of alpha-synuclein, which is more prone to clumping into the neurotoxic aggregates than the long form.

“The appendix is a hub for the accumulation of clumped forms of alpha-synuclein proteins,” the exact same aggregates found in Parkinson’s brains, said Bryan Killinger, the study’s first author and a postdoctoral fellow in Labrie’s lab.

Clumps of alpha-synuclein don’t seem to harm the appendix. But “the protein doesn’t like to stay put,” said Labrie. “It travels from neuron to neuron, including into the vagus nerve” from the appendix up to the brainstem. As it happens, where the vagus enters the brainstem is one of the first brain regions to contain alpha-synuclein. And it’s probably no coincidence that cutting the vagus, as was once done to cure ulcers (it didn’t), reduced the risk of Parkinson’s, according to previous studies. “That was an aha moment,” Beck said. “It added weight to the gut-brain hypothesis of Parkinson’s.”

The presence of pathogenic forms of alpha-synuclein in the appendixes of people both with and without Parkinson’s shows that a “second hit” — which Labrie has started to look for — is necessary for the disease to develop: More than 99 percent of people manage to avoid Parkinson’s, appendix or not.

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It’s anyone’s guess what the second hit is. One hint, though, comes from the urban-rural divide in the protective effect of appendectomy, as well as the finding that it’s protective only in people with a non-genetic family history of the disease. A non-genetic cause with a family history suggests shared environments, not shared DNA.

Those facts suggest that alpha-synuclein in the appendix becomes more abundant, more pathogenic, or more upwardly mobile in the presence of something found in the countryside more than cities. Pesticides, well water, and farming, for instance, have been linked to a higher risk of Parkinson’s since 1998.

For new drug possibilities, the Van Andel team suggests compounds that cut alpha-synuclein in the gut. Alpha-synuclein-targeted drugs to treat Parkinson’s have been in development for years, but almost always with the idea of delivering them to the brain. It would almost certainly be easier and safer to target the gut.

As it happens, compounds called metalloproteases, which have been tested against cancer (unsuccessfully), might be repurposed to inhibit enzymes that cut alpha-synuclein into the short, clumping, disease-causing form. It might “be an effective strategy for the treatment or even prevention” of Parkinson’s, the scientists wrote.

A more karmic argument for the appendix-Parkinson’s link: Dr. James Parkinson (1755 to 1824), for whom the disease is named, was the first English physician to describe a case of appendicitis.