Development of Parkinson’s Disease Could Begin in Intestinal Cells, New Study Suggests

Iqra Mumal, MSc avatar

by Iqra Mumal, MSc |

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α-synuclein in intestinal cells

New research shows that alpha-synuclein is expressed in the enteroendocrine cells (EECs) of the intestine, which are directly connected to nerves that contain α-synuclein, forming a neural circuit between the gut and the nervous system.

In this manner, external toxins and other environmental influences could aid in the misfolding of α-synuclein in EECs, causing them to be transmitted from the gut to the brain and eventually leading to Parkinson’s disease.

The study, “α-Synuclein in gut endocrine cells and its implications for Parkinson’s disease,” was published in the journal JCI insight.

Parkinson’s disease is characterized by the presence of Lewy bodies, which are abnormal aggregates of proteins found within neurons of the brain. It is these aggregates that are linked to the degeneration of neurons, which cause the classical symptoms of Parkinson’s, such as tremors and irregular limb movement. The main component of Lewy bodies is α-synuclein, which is a protein that has the tendency to misfold and aggregate into clumps.

Recently, studies have shown that misfolded α-synuclein can be transmitted between cells, which allows them to cause normal α-synuclein to misfold and aggregate in previously normal cells.

Some researchers have suggested that the process of α-synuclein aggregation may begin in the enteric nervous system, which is a system of neurons that govern the functions of the gastrointestinal tract, as α-synuclein aggregates have been shown to appear in enteric nerves before the brain.

Also, Parkinson’s patients have an altered gut microbiome, and studies have suggested that environmental toxins may be involved in the development of Parkinson’s disease.

For the most part, the enteric nervous system is separated by the contents of the intestine except for the presence of EECs, which have part of their surface in the gut intestine but are also connected to neurons of the enteric nervous system. Researchers at Duke University previously demonstrated that EECs have very similar features to neurons, which led them to hypothesize whether EECs are involved in neurotransmission.

Therefore, this study was conducted to determine whether EECs express alpha-synuclein and if they do, what their role is in the initiation of the α-synuclein aggregation leading to Parkinson’s.

Results from the study showed that EECs in both the large and small intestine express α-synuclein in mice and humans. And, α-synuclein was found in multiple types of EECs that were dispersed throughout the intestine.

Interestingly, EECs that had α-synuclein were located near enteric neurons that also expressed α-synuclein, which corroborated the hypothesis that α-synuclein in the EECs spread to enteric neurons and eventually to the brain. Additionally, α-synuclein was not present in every nerve that was connected to α-synuclein-containing EECs, which indicates that α-synuclein does not move from the nervous system to the EECs.

As an added bonus, the fact that this finding was consistent between humans and mice is encouraging for the use of mouse models to study Parkinson’s disease.

When taken together, the results of this study suggest that the surface of EECs that is exposed to intestinal contents can come in contact with ingested toxins, which can then be taken up by EECs and cause misfolding and aggregation of α-synuclein inside the cells. Since EECs are in contact with enteric nerves, the misfolded α-synuclein can be transmitted to the nerves, where it can lead to the formation of Lewy bodies, and eventually to the manifestation of Parkinson’s disease.

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