Scientists led by the Van Andel Research Institute in Michigan scoured two large patient registries, encompassing data from 1.7 million people, and made an astounding discovery: People who have their appendixes removed early in life reduce their risk of developing Parkinson’s disease by 19% to 25%.
But why? The research, published in the journal Science Translational Medicine, points to a link between the gastrointestinal tract, the immune system and the onset of Parkinson’s. And while the researchers stopped short of suggesting appendectomies as preventative measures, they did point out that the finding could lead to new therapies for Parkinson’s that target the GI tract.
The key to the link between the gut and Parkinson’s is a group of proteins called alpha-synucleins. The abnormal folding of these proteins is known to cause the onset and progression of Parkinson’s. The Van Andel researchers studied appendix tissue samples from healthy people and from Parkinson’s patients and discovered "a remarkable abundance of clump forms of alpha-synuclein," said Viviane Labrie, Ph.D., assistant professor and senior author of the paper, during a call with journalists.
Clumped alpha-synuclein protein can move from neuron to neuron and there is "experimental evidence that it can travel up the nerve that connects the G.I. tract to the brain," Labrie said. "And if it were to enter the brain, it can seed and spread from there and have neurotoxic effects that could eventually lead to Parkinson’s disease."
There were some surprising findings in the appendix tissue samples, Labrie’s colleagues said during the call. For example, the alpha-synuclein clumps were "equally abundant" in normal appendix tissue and inflamed samples, said co-author Patrik Brundin, M.D., Ph.D., during the call. And people who were younger than 20 had just as many clumps as did people between age 50 and 80, negating any hypothesis that abnormal protein aggregates multiply with age.
In 2016, a team at Caltech published evidence that changes in the gut microbiome affect the onset of Parkinson’s, as well as the severity. That work inspired the formation of Axial Biotherapeutics, which is developing microbiome-targeted therapies to treat central nervous system disorders.
When asked whether there’s a link between the Caltech discovery and alpha-synuclein clumps, Brundin said "microbiome perturbations could be one of the triggers for the synuclein clumping in the gut."
More research is needed to clarify that connection between the microbiome, the appendix and Parkinson’s, but Labrie suggested that the immune system may play an important role. That’s because the appendix is a repository of cells that recognize pathogens and mobilize an immune response to them. The appendix "also is important in regulating … the gut bacteria," she explained. Therefore, elevated levels of alpha-synuclein "could be hypothesized to be basically the immune regulation function," she said.
The new findings could boost the search for effective Parkinson’s treatments. The disease affects 1 million Americans and its prevalence is expected to double by 2040, the researchers said.
Several companies are already working on Parkinson’s therapies that target alpha-synuclein. They include Philadelphia-based Enterin, which raised $12.7 million last year to advance its drug targeting the protein.
The Van Andel researchers hope their ongoing studies will point to new ways of combatting the disease. One priority will be to try to figure out what distinguishes healthy people with alpha-synuclein clumps in their appendixes from those who go on to develop Parkinson’s.
Said Labrie, "There’s potential for G.I. tract-based therapies that could block the formation and spread of alpha-synuclein clumps as future, early and preventative treatments for Parkinson’s disease."
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