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Parkinson’s May Originate From Alpha-Synuclein Migrating From the Gut, Rat Study Shows

gut Parkinson's alpha-synuclein

New experimental evidence collected from rats shows that alpha-synuclein — the protein that causes Parkinson’s disease — can travel from the intestines to other organs, such as the heart and brain.

These findings, reported in the study “Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats,” provide further support to the hypothesis that the development of Parkinson’s disease is directly linked to the intestinal system.

The study was published in Acta Neuropathologica.

A hallmark feature of Parkinson’s is the progressive degeneration of brain cells due to the accumulation of toxic clumps of alpha-synuclein, called Lewy bodies.

Prior work in postmortem human brains has shown that the misfolded protein primarily accumulates in brain areas controlling movement, which explains the characteristic motor symptoms associated with the disease. But that work also revealed the protein’s accumulation in the vagus nerve – which connects the brain to the gut.

This led to the theory that Parkinson’s progression could require communication between the gut and the brain.

To further explore this association, researchers from Aarhus University and its clinical center, in Denmark, conducted a new study in rats. The team used rats that were genetically modified to produce excessive amounts of alpha-synuclein, and which were susceptible to accumulating harmful versions of the protein in nerve cells. Human alpha-synuclein or an inactive placebo was injected into the small intestines of these rats.

With this approach, the investigators found that both groups of rats — those injected with alpha-synuclein or placebo — had high levels of the protein in the brain. However, only those injected with alpha synuclein showed Parkinson’s characteristic clump build-up patterns, which affected the motor nucleus and substantia nigra in the brain.

“After two months, we saw that the alpha-synuclein had travelled to the brain via the peripheral nerves with involvement of precisely those structures known to be affected in connection with Parkinson’s disease in humans,” Per Borghammer, an Aarhus University professor and the study’s senior author, said in a press release written by Mette Louise Ohana.

“After four months, the magnitude of the pathology was even greater. It was actually pretty striking to see how quickly it happened,” Borghammer said.

Alpha-synuclein also was found to accumulate in the heart and stomach, which suggests a secondary propagation pathway. That pathway likely is mediated by the celiac ganglia, which are abdominal nerve bundles that innervate the gastrointestinal tract.

A recent study conducted by researchers at Johns Hopkins University School of Medicine revealed similar data, but in mice. The Hopkins team also found that, when they injected an altered form of alpha-synuclein in the intestine of mice, it would first accumulate in the vagus nerve and subsequently spread throughout the brain.

With the findings from the new study, researchers now have more detailed evidence on how the disease most likely spreads.

This may put the scientific community one step closer toward developing more effective medical strategies to halt the disease, Borghammer said.

“For many years, we have known that Parkinson patients have extensive damage to the nervous system of the heart, and that the damage occurs early on. We’ve just never been able to understand why. The present study shows that the heart is damaged very fast, even though the pathology started in the intestine, and we can continue to build on this knowledge in our coming research,” he said.

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Key Protein in Parkinson’s – Alpha-synuclein – Travels from Gut to Clump in Brain, Study Reports

gut and alpha-synuclein

Altered forms of the alpha-synuclein protein travel along the vagus nerve from the gut to the brain where they accumulate, according to a study in mice. It also suggests that blocking this transport could prevent the progression of Parkinson’s disease.

The work lends support to theories that Parkinson’s begins in the gastrointestinal tract.

“This is an exciting discovery for the field and presents a target for early intervention in the disease,” Ted Dawson, MD, PhD, one of the study’s senior authors, said in a press release.

Transneuronal Propagation of Pathologic a-Synuclein from the Gut to the Brain Models Parkinson’s Disease” was published in the journal Neuron.

Parkinson’s is characterized by the buildup of alpha-synuclein in protein inclusions in the brain called Lewy bodies. Prior work in postmortem human brains has shown that misfolded alpha-synuclein accumulates in brain areas controlling the gut. This led researchers to hypothesize that Parkinson’s progression requires communication between the gut and the brain.

Aiming to test whether misfolded alpha-synuclein travels along the vagus nerve — the longest nerve in the autonomic nervous system that connects the stomach and small intestine to the brain — researchers at Johns Hopkins University School of Medicine injected 25 micrograms of synthetic misfolded alpha-synuclein fibrils into the muscle layers of the duodenum (the first part of the small intestine) and the pylorus (the opening from the stomach into the duodenum) of healthy mice.

Over the course of 10 months, the scientists then found that alpha-synuclein began to accumulate in the vagus nerve to subsequently spread throughout the brain, seen by the detection of the altered form of this protein there.

One of the brain areas with misfolded alpha-synuclein was the substantia nigra pars compacta (SNpC), where the scientists found a gradual loss of dopamine-producing nerve cells, as typically seen in people with Parkinson’s. The levels of dopamine and its by-products were also lower in the striatum, a brain area connected to the SNpC and a key component of the motor system.

Surgically cutting the vagus nerve before injecting mice with misfolded alpha-synuclein led to none of the signs observed in animals with an intact vagus nerve, namely alpha-synuclein transport, loss of dopaminergic neurons, and lower dopamine levels.

Mice genetically engineered to lack the alpha-synuclein protein also showed no evidence of transmission to the brain after being injected with the protein’s misfolded form.

Subsequent experiments assessed whether transmission of pathological (disease-causing) forms of alpha-synuclein from the the gut to the brain caused behavioral changes.

Seven months after modified alpha-synuclein injections, the animals’ ability to build nests was analyzed as a way to assess their motor skills. Mice injected with misfolded alpha-synuclein that had an intact vagus nerve had lower scores than those with cut nerves: their nests were smaller and messier. These animals also used less than half a gram of nesting material, in contrast to the 2.5 grams used by the animals with severed nerves.

These mice also had higher anxiety levels than those with a damaged vagus nerve or genetically modified to lack alpha-synuclein, as observed in a test of how long the animals would spend exploring a large open box.

Other tests indicated that injecting modified alpha-synuclein and having intact nerves led to motor dysfunction, reduced grip strength, impaired learning, and caused olfactory problems and depression-like symptoms.

“Our results support the theory that [Parkinson’s] could begin in the gastrointestinal tract and spread through the vagus nerve to the brain,” the researchers wrote.

“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,” Dawson, who also the director of the Johns Hopkins Institute for Cell Engineering, added.

The team is now planning to study which parts of the vagus nerve are key for the travel of the misfolded protein, as a way to find how to stop this process.

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