Gut immune cells may help Parkinson’s spread from the belly to the brain
Mouse study reveals how specialized cells inadvertently ferry toxic protein
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- Parkinson's may originate in the gut, with muscularis macrophages inadvertently spreading toxic alpha-synuclein proteins to the brain.
- Early gastrointestinal issues like constipation often precede motor symptoms, linked to alpha-synuclein accumulation in gut nerves.
- Reducing these gut immune cells in mice limited disease spread and symptoms, suggesting a potential therapeutic target.
Parkinson’s disease may actually begin deep in the gut, where immune cells meant to protect the body inadvertently help toxic proteins make their way to the brain, according to a new study.
Researchers at the UK Dementia Research Institute at University College London (UCL) have identified a specific type of immune cell — muscularis macrophages — as a key player in this process. While these cells normally maintain nerve health, researchers found they can instead harbor clumps of alpha-synuclein, the toxic protein linked to Parkinson’s, and facilitate its spread toward the central nervous system.
In mouse models, reducing the levels of these gut-based immune cells significantly limited the spread of the disease to the brain and eased motor symptoms. This discovery offers a biological roadmap for a theory scientists have chased for decades: that Parkinson’s starts in the digestive tract years before the first tremor appears.
The gut-brain connection in Parkinson’s
“Understanding how Parkinson’s begins in the body could allow us to develop simple blood tests to screen for it, enabling diagnosis long before damage to the brain starts,” Tim Bartels, PhD, group leader at the UK Dementia Research Institute and co-lead author of the study, said in a press release from UCL. “Having the ability to detect and manage Parkinson’s before it even reaches the brain could have a huge impact for those affected.”
The study, “Intestinal macrophages modulate synucleinopathy along the gut–brain axis,” was published in Nature.
Parkinson’s disease is caused by the progressive loss of nerve cells in the brain responsible for producing dopamine, a key chemical messenger that helps control movement. The accumulation of toxic clumps of misfolded proteins, particularly alpha-synuclein, is thought to be the primary driver of this nerve cell damage
For decades, researchers have hypothesized that Parkinson’s may begin outside the brain. One leading theory suggests the disease could start in the enteric nervous system, the network of nerves embedded in the gut wall. Supporting this idea, clumps of alpha-synuclein have been found in the gut of people with Parkinson’s, and imaging findings suggest this protein buildup may spread from the intestine to the brain.
Previous studies have also found that 50% to 90% of people who later develop Parkinson’s experience gastrointestinal problems, such as chronic constipation, years or even decades before motor symptoms appear.
Together, these findings support the concept of a gut-brain axis in Parkinson’s disease. However, exactly how alpha-synuclein begins to accumulate in the gut and then travels to the brain has remained largely unclear, the researchers noted.
In this study, the team first confirmed that, in a mouse model of Parkinson’s, abnormal alpha-synuclein accumulated early in nerve cells of the enteric nervous system. Only later did the protein appear in the brain, primarily accumulating in the dorsal motor nucleus of the vagus nerve, which directly connects the brain to the digestive tract.
How immune cells inadvertently spread disease
To test whether alpha-synuclein in the gut could drive disease in the brain, the researchers injected misfolded alpha-synuclein isolated from the brains of people who had died with Parkinson’s into the small intestines of mice. They then tracked the protein’s movement through the body.
Alpha-synuclein first built up in nerve cells of the enteric nervous system, where it caused slowed movement of food through the intestines — a change similar to constipation commonly seen in people with Parkinson’s. Over time, the abnormal alpha-synuclein appeared in connected nerve pathways leading from the gut to the brain. Eventually, it reached brain regions involved in movement control, including areas containing dopamine-producing neurons. This spread was accompanied by the loss of those neurons and the development of movement problems in the animals.
The researchers found that in the gut, muscularis macrophages — immune cells that normally protect gut nerves by clearing harmful material — took up unusually large amounts of alpha-synuclein, likely to remove it. Inside these cells, the toxic protein accumulated in structures called lysosomes, which act as the cell’s recycling and waste-disposal centers.
As the toxic protein continued to build up, lysosomes began to show signs of dysfunction. The alpha-synuclein inside these cells also showed a greater tendency to clump, suggesting that these immune cells may inadvertently help sustain toxic forms of the protein rather than eliminate them.
These stressed macrophages also released signals that activated T-cells, immune cells that help coordinate the body’s defenses. After being activated in the gut, T-cells entered the bloodstream and were later detected in the brain, where the researchers suggest they may promote inflammation and contribute to disease progression.
Importantly, when the researchers reduced the number of muscularis macrophages before injecting alpha-synuclein into the small intestine of mice, much less toxic alpha-synuclein reached the brain. These mice also showed less nerve cell damage and milder motor symptoms.
“Our study shows that immune cells are not bystanders in Parkinson’s; these gut macrophages are responding, albeit in a dysfunctional way,” said Soyon Hong, PhD, group leader at the UK Dementia Research Institute and co-lead author of the study. “This presents an opportunity to think about how we can boost the function of the immune system and these cells, so that they respond in the correct manner and help to slow or stop the spread of disease.”
