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.
source:
http://www.sciencemag.org/news/2018/10/seeds-parkinson-s-disease-may-hide-appendix
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