Mouse study sheds light on alpha-synuclein buildup in the gut

Researchers explore why extracellular vesicles accumulate in the GI tract

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A rodent is seen an an oversized human hand, flanked by vials of serum.

Recent research in mice has revealed possible mechanisms by which alpha-synuclein protein is transported from blood cells in circulation to the gastrointestinal (GI) tract, where the protein is then thought to travel to the brain to drive Parkinson’s disease.

Cellular carriers called extracellular vesicles (EVs) released from red blood cells (RBCs) in mice were found to contain alpha-synuclein. Their injection into the bloodstream led to the accumulation of the protein in the GI tract, including near nerve cell endings that communicate with the brain.

Changes in gut permeability, mediated by alterations to the microbiome —the collection of microorganisms that reside in the digestive tract — might partly explain why the EVs accumulate in certain areas of the gut.

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“By demonstrating the transportation of [alpha-synuclein] through RBC-EVs to the [GI tract] … this research highlights a potential mechanism by which RBC [alpha-synuclein] may impact [Parkinson’s] initiation and/or progression,” the researchers wrote.

The study, “Erythrocytic α-Synuclein and the Gut Microbiome: Kindling of the Gut-Brain Axis in Parkinson’s Disease,” was published in Movement Disorders.

In Parkinson’s, a misfolded version of alpha-synuclein toxically accumulates in the brain. These toxic clumps (aggregates) demonstrate a unique ability to propagate, or spread from one area to another, a process thought to be key to the progressive neurodegeneration that characterizes the disease.

EVs, which carry cargo cell-to-cell to facilitate cellular communication, are believed to be one way that alpha-synuclein aggregates propagate. EVs may carry the toxic protein from one place in the brain to another.

Alpha-synuclein in the gut may spread to the brain

Alpha-synuclein clumps also can be observed in tissues outside of the brain, including the GI tract. It has been proposed that early alpha-synuclein buildup in the gut may contribute to its spread into the brain, possibly through its uptake into nerve fibers that innervate the gut (vagal nerve).

However, it is not known where the toxic alpha-synuclein in the GI tract comes from in the first place.

In the recent study, scientists investigated the possibility that EVs from RBCs in circulation, which are are known to contain high levels of alpha-synuclein, might contribute to the buildup of the protein in the gut.

In healthy mice, alpha-synuclein was found throughout the GI tract, but the protein was not seen in the GI tract of mice lacking SNCA, the gene responsible for producing alpha-synuclein.

Injection of alpha-synuclein directly into the bloodstream of healthy mice did not cause increases of the protein in the GI tract. But when RBC-EVs, which were found to contain alpha-synuclein, were injected, alpha-synuclein was transported rapidly from the blood to organs throughout the body, including in the intestines.

When mice lacking SNCA — and not producing their own alpha-synuclein — were injected with RBC-EVs from a Parkinson’s mouse model or Parkinson’s patients, the protein was was found in the GI tract, “further demonstrating that [alpha-synuclein] can be brought to the [GI tract] via RBC-EVs,” the researchers noted.

In healthy mice, the injected RBC-EVs could be seen to later travel to the vagus nerve endings in the GI tract, which also was seen in mice lacking SNCA. Lab studies indicated that nerve cells are able to take up and internalize the blood vesicles, supporting a potential mechanism by which alpha-synuclein in the gut may lead to its buildup in the brain.

Permeability of the gut-vascular barrier

Certain areas of the GI tract seemed to see a greater accumulation of alpha-synuclein. Researchers found this likely was related to higher permeability in the cellular barrier separating the gut from the bloodstream, called the gut-vascular barrier, or GVB.

Gut permeability can be influenced by the constellation of bacteria, viruses, and fungi that populate the gut, known as the gut microbiome.

Indeed, the microbiome showed some alterations in a mouse model of Parkinson’s, including an abundance of bacteria that produce a metabolite called butyrate. When mice were treated with butyrate for a month, the gut became less permeable, and RBC-EVs were not taken up as readily in the GI tract.

Moreover, evidence suggested that alpha-synuclein in the gut itself also increases permeability.

“In summary, we have identified a novel source of gut [alpha-synuclein],” the researchers wrote, noting that it is possible the protein also comes from other as-yet-uninvestigated sources.

Still, “the precise mechanism underlying the spreading of [alpha-synuclein] to the [brain and spinal cord] remains to be investigated in future studies,” the team wrote. While the vagus nerve is one possibility, it also is possible that alpha-synuclein reaches the brain through general circulation. “Further research is required to ascertain the specific mechanisms by which RBC-EVs reach neural structures.”