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VAI Voice

The Official Blog of Van Andel Institute
27 Nov 2017

Can alpha-synuclein in the gut impact the brain?

Scientists have a gut feeling about Parkinson’s disease.

Namely, that it may not start in the brain, the organ most often associated with disease. Instead, growing evidence suggests it’s the digestive system that could be an important starting point for the disorder, which slowly robs an estimated seven to 10 million people worldwide of their ability to move.

In fact, some of the earliest symptoms of the disease aren’t related to movement at all; years or even decades before diagnosis, people with Parkinson’s often experience a slate of non-motor symptoms such as gastrointestinal issues and loss of sense of smell.

“Parkinson’s is an incredibly complex disease that likely has an equally complicated set of factors that cause its onset and progression, such as genetic and epigenetic risk, chronic inflammation and environmental triggers,” said Dr. Viviane Labrie, a neuroscientist at Van Andel Research Institute and senior author of a recently published review on the subject. “It’s like dropping grains of sand on a scale—eventually, if you add enough of them, the whole thing will tip.”

A systematic breakdown
Parkinson’s is thought to be the result of a faulty form of the protein alpha-synuclein, which clumps together and clogs up the inner workings of cells. Under normal circumstances, cells are able to clear out these harmful proteins, preventing damage and keeping themselves healthy.

In the earliest stages of disease, however, this system goes awry, allowing alpha-synuclein to remain, where it causes cell damage and death. Clumps of alpha-synuclein, called Lewy bodies, are a hallmark sign of Parkinson’s and are commonly found in the brains and digestive tracts of people with the disease.

Where does faulty alpha-synuclein come from?
Many vertebrates, humans included, have alpha-synuclein throughout their tissues, with some of the highest concentrations being found in the brain. Most of the time, alpha-synuclein isn’t a problem—the trouble arises when the protein is coaxed to change its shape, transforming it from a normal part of the body’s day to day function into a toxic version of itself.

“We aren’t entirely sure what causes this change, but we know that once it does occur, faulty alpha-synuclein can act as a template that prompts the same alteration in normal proteins,” said Dr. Bryan Killinger, a postdoctoral fellow in Labrie’s lab and first author of the review article. “We wondered if there could be other sources for abnormal alpha-synuclein.”

“A very tangled web”
Because alpha-synuclein also is present in the tissues of other vertebrates, Killinger and Labrie began combing through the scientific literature to look for hints of possible dietary influences, such as meat consumption.

They were interested in exploring whether flawed alpha-synuclein from an external source could cause proteins in a person’s gut to also change.

“By itself, faulty alpha-synuclein from external sources is unlikely to cause Parkinson’s disease,” Labrie says. “We believe there must be additional factors involved in advancing the chain reaction that eventually leads to neurodegeneration. Alpha-synuclein from an external source may simply bring a potential issue to the doorstep, but other factors such as genetic risk, aging and environment influences are needed to pass the threshold and progress toward Parkinson’s disease.”

Existing research linking Parkinson’s disease and diet is relatively limited but, Labrie and Killinger say, there have been few studies focused specifically on external sources of alpha-synuclein.

“It’s a difficult idea to investigate, in part because Parkinson’s disease progresses so slowly that a person may not notice symptoms until decades after the disease actually begins on a cellular level,” Killinger adds. “Couple that with the array of factors that we know affect disease risk and you have a very tangled web.”

Traveling the “superhighway”
But if all of this is happening in the gut, how does it impact the brain? Enter the vagus nerve—one of the longest nerves in the human body and a “superhighway” to the brain.

Evidence suggests that alpha-synuclein spreads by moving from cell to cell, leaving behind defective copies along the way. In the gut, scientists believe it reaches the vagus nerve and travels up its length to the brain, where it eventually infiltrates an area chock full of neurons, some of which produce dopamine, a chemical required for voluntary movement. These cells become packed with clumps of alpha-synuclein and die off over many years, starving the brain of dopamine and leading to Parkinson’s hallmark motor symptoms.

By studying the theory that the gastrointestinal tract may be involved in the origins of Parkinson’s disease, Labrie and Killinger hope to clarify the gut’s role and leverage their findings to better define risk factors for the disease.

“We believe Parkinson’s is the result of a lifetime of influences, not just one singular cause,” Labrie said. “If we want to have a better picture of what’s going on behind the scenes and find ways to mitigate risk, we need to look at where the disease may begin.”

For more information on the Labrie Lab and their research, please visit their website here.