New Evidence Suggests Parkinson's Disease Might Not Start in The Gut

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New Evidence Suggests Parkinson's Disease Might Not Start in The Gut

Animal study presents best evidence to date that Parkinson’s begins in the gut

A new study adds further evidence to a growing number of research breakthroughs, suggesting that Parkinson's disease (PD) comes from the intestine and not the brain. New research results in mice suggest that Parkinson's disease may begin in the gut, which may explain why most patients with Parkinson's disease complain of constipation and gut-related symptoms before other symptoms appear.
Route of Parkinson's disease-causing protein propogation in mice. Credit: Ted Dawson
The researchers noted that people with PD often report digestive problems up to 10 years before they notice tremors. There is also evidence that people with Parkinson's disease have different intestinal bacteria than other healthy adults.

A large and rigorous animal study conducted by scientists at Johns Hopkins University showed that poorly folded proteins that could cause Parkinson's disease could come from the gut and travel to the brain through the vagus nerve. This research is based on a compelling body of evidence showing a link between the intestine and the brain in the disease and suggests possible new treatment options.

Further proof that Parkinson's disease starts in the intestines
Parkinson's disease is characterized by the progressive cell death of brain neurons that secrete dopamine, which may be due to the aggregation of poorly folded spherical clusters of alpha-synuclein protein. These toxic protein clusters are often referred to as Lewy bodies.

For several decades, scientists had known that these Lewy bodies were present in the gastrointestinal tract of patients with Parkinson's disease, but it was only after the publication of a series of influential texts in the early 2000s of a strong hypothesis that this idea was accepted

German scientist Heiko Braak and his team hypothesized that the disease started in the intestine and that harmful Lewy bodies entered the brain through the vagus nerve. Braak's hypothesis, as it is known today, is still an idea that divides researchers in the field of Parkinson's disease research, with as many skeptics as believers.

One of the first experimental challenges in testing Braak's hypothesis was to verify whether Lewy bodies could actually spread directly from the intestine to the brain. A study conducted in 2014 on rats did indeed demonstrate that this spread was indeed possible, but this new Johns Hopkins research is the most rigorous evidence produced to date. She shows that these poorly folded proteins can pass from the intestine to the brain, but that this propagation can also induce pathological signs of Parkinson's disease.

Protein spread was stopped when the vagus nerve was severed
This study began with the injection of poorly folded synthetic alpha-synuclein into the intestines of healthy mice, followed for 10 months. Analysis of brain tissue at several points during this 10-month period revealed that alpha-synuclein was first aggregated to the point where the vagus nerve was connected to the intestine and then spread throughout the brain. Even more interestingly, the spread of alpha-synuclein proteins in the brain was stopped when the animals' vagus nerves were severed.

The next step in this research was to determine whether this spread of alpha-synuclein from the intestine to the brain conferred behavioural changes similar to those observed in Parkinson's disease. In a number of different behavioural studies commonly used to assess Parkinson's disease in animals, mice inoculated with poorly folded alpha-synuclein consistently had lower results than mice in the control group.

Most importantly, the results of a third experimental group of mice, inoculated with poorly folded alpha-synuclein, but with severed vagal nerves, showed similar scores to those of the control group. This suggests that Parkinson's disease could originate in the intestine and that blocking this transmission route could effectively prevent the onset of the disease.

Interesting results but not definitive evidence
"These results provide further evidence of the role of the intestine in Parkinson's disease and provide us with a model to study the progression of the disease from the beginning," said Ted Dawson, one of the authors of the new study. "This is an exciting discovery and a target for early intervention in this disease.

This new study is far from being a definitive proof of the origins of Parkinson's disease in the intestine and brain. A recent article presenting the arguments for and against the origins of Parkinson's disease in the intestine concluded that there was a remarkable body of evidence against this bold hypothesis.

There is no doubt that we need more research, especially in humans, but the work of the Johns Hopkins team is a positive step in developing potential new treatments for this devastating disease.