Parkinson’s originates from the gut—Researchers at Johns Hopkins Medicine have found evidence that Parkinson’s originates in the cells of the intestine and travels through neurons in the body to the brain. The study conducted in mice, published in the journal ‘Neuron’, offers a new and more accurate model to test treatments that could prevent or stop the progression of this disease.
“These findings provide further evidence of the role of the gut in Parkinson’s disease, and provide us with a model to study the progression of the disease from the beginning,” says Ted Dawson, director of the Johns Hopkins Institute of Cellular Engineering and professor of neurology at the Johns Hopkins University School of Medicine.
Parkinson’s disease is characterized by the accumulation of a misfolded protein, called alpha-synuclein, in brain cells. As most of these proteins begin to cluster, they cause the death of nerve tissues, leaving behind large swathes of dead brain matter known as Lewy bodies. And as brain cells die, they affect a person’s ability to move, think, or regulate emotions.
The new study is based on observations made in 2003 by the German neuroanatomist Heiko Braak, who showed that people with Parkinson’s disease also had accumulations of the folded alpha-synuclein protein in the parts of the central nervous system that control the intestine.
The appearance of proteins harmful to neurons is consistent with some of the first symptoms of Parkinson’s, such as constipation
The appearance of these proteins harmful to neurons is consistent with some of the early symptoms of Parkinson’s disease, which include constipation, explains Han Seok Ko, an associate professor of neurology at the Johns Hopkins University School of Medicine. Braak hypothesized that Parkinson’s disease progressed to the nerves that connect the intestine and the brain, to climb as if by a ladder.
The increasing number of evidences has involved the brain-gut connection in the onset of Parkinson’s disease. The researchers were very curious to know if the misfolded alpha-synuclein protein could travel along the vagus nerve, which functions as an electrical cable from the stomach and small intestine to the base of the brain.
To prove it, the researchers injected 25 micrograms of misfolded synthetic alpha-synuclein created in the laboratory into the intestines of dozens of healthy mice. They took samples and analyzed the brain tissue one, three, seven and 10 months after the injection. Over the course of the 10-month experiment, the researchers saw evidence that alpha-synuclein began to build where the vagus nerve connected to the intestine and continued to spread throughout all parts of the brain.
The researchers then performed a similar experiment, but this time they surgically cut the vagus nerve in a group of mice and injected their intestines with the misfolded alpha-synuclein.
After a seven-month examination, the researchers found that mice with cut vagus nerves showed none of the signs of cell death in mice with intact vagus nerves. The cut nerve seemed to stop the advances of the misfolded protein, says Dawson.
The researchers also wanted to know if these physical differences in the progression of the disease led to behavioral changes. To test this, they evaluated the behavior of three groups: mice injected with misfolded alpha-synuclein, mice injected with folded alpha-synuclein with cut vagus nerves and control mice without injection and intact vagus nerves. The researchers analyzed the tasks they used to distinguish signs of Parkinson’s disease in mice, such as building nests and exploring new environments.
The researchers observed for the first time that mice build nests in their enclosure as a test for fine motor skill, which is commonly affected by Parkinson’s disease in humans.
Seven months after the injection, the mice that received the injection of misfolded alpha-synuclein scored consistently lower in the construction of the nest.
In addition, while the majority of mice used all of the 2.5 grams of material provided, the group of mice that received the alpha-synuclein injection used less than half a gram of the nesting material. “According to the symptoms of Parkinson’s disease in humans, the fine motor control of the mice deteriorated as the disease progressed,” says Ko.
In another experiment that analyzed mice for symptoms similar to Parkinson’s disease in humans, the researchers measured levels of anxiety by analyzing how they responded to new environments.
For this test, the researchers placed the mice in a large open box where a camera could track their exploration. Healthy mice are curious and will spend time researching each part of a new environment. However, mice affected by cognitive decline are more anxious, which makes them more likely to stay towards the protected edges of a box.
The research team discovered that control mice and mice whose vagus nerves were cut to protect against Parkinson’s disease spent between 20 and 30 minutes exploring the center of the box.
Meanwhile, the mice that received the incorrectly folded alpha-synuclein injection but had intact vagus nerves spent less than five minutes, indicating higher levels of anxiety that are consistent with the symptoms of Parkinson’s disease according to the researchers.
In general, the results of this study show that misfolded alpha-synuclein can be transmitted from the intestine to the brain in mice along the vagus nerve, and blocking the route of transmission could be key to preventing the physical and cognitive manifestations of Parkinson’s disease.
Parkinson’s disease is a disease of the central nervous system (brain) that progressively causes movement abnormalities such as tremors, slow and difficult movements (akinesia), and stiffness of the whole body.
Parkinson’s disease is a degenerative brain disease. Some populations of neurons degenerate, which translates into a difficulty triggering voluntary movements.
This disease, which affects 2% of the population beyond 65 years, evolves slowly and the first signs, namely tremors, difficulty to perform movements and rigidity, appear only in five to ten years after the beginning of the degeneration of the neurons.