An important and rigorous new animal study led by scientists at Johns Hopkins University has demonstrated how the misfolded proteins thought to cause Parkinson's disease may originate in the gut, and travel up to the brain via the vagus nerve. This research builds on a compelling body of evidence pointing to a gut-brain connection in the disease and hints at possible new treatment pathways.
Parkinson's disease is characterized by the progressive cell death of the brain's dopamine-secreting neurons that is believed to be caused by the aggregation of spherical misfolded clumps of the protein alpha-synuclein. These toxic protein aggregates are often referred to as Lewy bodies.
For several decades scientists have known these Lewy bodies could be found in the gastrointestinal tracts of Parkinson's disease patients, but it wasn't until a series of influential papers were published in the early 2000s that a strong gut-brain hypothesis was put forward. German scientist Heiko Braak and his team hypothesized the disease originated in the gut, and the damaging Lewy bodies subsequently traveled up into the brain via the vagus nerve. The Braak hypothesis, as it is now known, is still a divisive idea in the field of Parkinson's research, with as many skeptics as believers.
One of the first experimental challenges in verifying the Braak hypothesis is of course establishing whether Lewy bodies can actually spread directly from the gut to the brain. A 2014 rat study effectively demonstrated this spread is indeed possible, but this new Johns Hopkins research is the most rigorous evidence produced to date, demonstrating that not only can these misfolded proteins move from the gut to the brain, but that spread can also induce key pathological signs of Parkinson's disease.
The study began by injecting synthetic misfolded alpha-synuclein into the guts of healthy mice and tracking those animals for 10 months. Analyzing brain tissue at several points over the 10-month period revealed the alpha-synuclein first aggregated at the point the vagus nerve connected to the gut, and then eventually spread throughout the brain. Even more interesting, the spread of the alpha-synuclein proteins up into the brain was halted when the animals' vagus nerve was severed.
The next step in the research investigated whether this spread of alpha-synuclein from the gut to the brain conferred behavioral changes similar to those seen in Parkinson's disease. Across a number of different behavioral studies, commonly used to evaluate Parkinson's disease in animals, the mice seeded with the misfolded alpha-synuclein scored consistently lower than control group mice. Most importantly, however, the results of a third experimental group of mice, seeded with misfolded alpha-synuclein but with severed vagal nerves, showed scores similar to that of the control group. This suggests Parkinson's disease may originate in the gut, and blocking this transmission pathway could effectively prevent the onset of the disease.
"These findings provide further proof of the gut's role in Parkinson's disease, and give us a model to study the disease's progression from the start," says Ted Dawson, one of the authors of the new study. "This is an exciting discovery for the field and presents a target for early intervention in the disease."
This new study is nowhere near definitive or conclusive proof of the gut-brain origins of Parkinson's. A recent paper outlining the arguments for and against the gut origins of Parkinson's concluded there is a notable volume of evidence against this bold hypothesis. More work, especially in human subjects, is undeniably needed, but this work from the Johns Hopkins team is a positive step towards developing new potential treatments for this devastating disease.
The new research was published in the journal Neuron.
Source: Johns Hopkins Medicine
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