Mounting evidence is pointing to an association between the gut and Parkinson’s disease. New research coming out of Johns Hopkins University School of Medicine has added some weight to the connection and offered a new model for testing drugs aimed at treating the neurodegenerative disorder.
In mouse studies, Johns Hopkins scientists found that misfolded alpha-synuclein protein—which scientists believe accumulates in the brain and drives Parkinson’s—can travel from the gut to the brain. They published the findings in the journal Neuron.
Back in 2003, German neuroanatomist Heiko Braak and colleagues found that in postmortem samples of Parkinson’s patients, clumps of alpha-synuclein also appeared in the nervous system that controls the gut, known as the enteric nervous system. That made sense to them, because Parkinson’s patients often develop gastrointestinal disorders such as constipation long before they show any motor impairments that are characteristic of Parkinson’s. Braak hypothesized that Parkinson’s might originate in the gut.
But there was one big question: Are these alpha-synuclein deposits in the enteric nervous system the same ones found in the brain? In other words, do the aggregates actually travel? To answer this, Johns Hopkins neurologist Ted Dawson and colleagues injected synthetic misfolded alpha-synuclein into the guts of dozens of healthy mice.
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Dawson's team tested the animals' brain tissues at one, three, seven and 10 months after injection and found that the protein started building near the vagus nerve, which connects major organs with the brain, to the gut and continued to spread to the brain. The observation is consistent with what a Lund University-led team described in a 2014 study in the journal Acta Neuropathologica.
After the researchers cut the vagus nerve in one group of mice, the animals showed no signs of cell death that were observed in those with intact vagus nerves, the team said in a release.
But how does that translate into Parkinson’s-related behavioral changes? The researchers set out to answer that question by tasking the mice with nest building and exploring new environments.
Mice with the misfolded alpha-synuclein and intact vague nerves used far fewer nesting materials than did the control mice and those with severed vague nerves, and their nests were smaller and messier, according to the team. The animals’ motor control deteriorated as the disease progressed, similar to how Parkinson’s plays out in people, said Han Seok Ko, a study co-author, said in a statement.
In another test, the researchers put the mice in a large open box to see how they responded to a new environment. The healthy mice and those with their vagus nerves removed spent around 20 to 30 minutes exploring mostly the center of the box, while the others spent less than five minutes doing so and moved toward sheltered borders. That indicates mice that received alpha-synuclein and had intact vagus nerves were more anxious, a symptom consistent with Parkinson’s, the researchers said.
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Accruing evidence of the gut’s possible role in neurological disorders is the basis of several biotech startups. These include Axial Biotherapeutics, which recently netted $25 million to fund its programs that target the gut microbiome to treat Parkinson’s and autism. New York-based Kallyope is also leveraging the gut-brain axis to find small molecules for metabolic and neurological diseases.
Targeting alpha-synuclein is also a popular strategy in Parkinson’s research. AbbVie and Voyager Therapeutics recently expanded their partnership to use “vectorize” antibodies against the toxic protein clump. A team at Georgetown University found that Novartis’ blood cancer drug Tasigna might work for Parkinson’s after showing that the drug can reduce levels of alpha-synuclein clumps and increase the levels of dopamine in Parkinson’s patients’ brains.
Last fall, a team of scientists led by the Van Andel Research Institute found that people who have their appendixes removed early in life are also less likely to develop Parkinson’s. They also discovered alpha-synuclein clumps in the appendix tissue they examined.
Dawson’s team at Johns Hopkins had previously identified a protein called c-Abl as a suspected driver of alpha-synuclein clumping in Parkinson’s.
Dawson hopes his team’s latest discovery could offer a model to study Parkinson’s progression. The researchers are now planing to explore what parts of the vagus nerve allow the misfolded protein to travel to the brain and to investigate potential mechanisms to stop it. All told, the new evidence of a link between the gut and brain “presents a target for early intervention in the disease,” he said.