Parkinson's disease from the gut

Abstract

Parkinson's disease (PD) is a debilitating neurodegenerative condition associated with tremor, rigidity, dementia, and gastrointestinal symptoms such as constipation, nausea and vomiting. The pathological hallmarks of PD are Lewy bodies and neurites in the brain and peripheral nerves. The major constituent of Lewy bodies is the neuronal protein α-synuclein. Misfolding of α-synuclein confers prion-like properties enabling its spread from cell to cell. Misfolded α-synuclein also serves as a template and induces misfolding of endogenous α-synuclein in recipient cells leading to the formation of oligomers that progress to fibrils and eventually Lewy bodies. Accumulating evidence suggests that PD may arise in the gut. Clinically, gastrointestinal symptoms often appear in patients before other neurological signs and aggregates of α-synuclein have been found in enteric nerves of PD patients. Importantly, patients undergoing vagotomy have a reduced risk of developing PD. Experimentally, abnormal forms of α-synuclein appear in enteric nerves before they appear in the brain and injection of abnormal α-synuclein into the wall of the intestine spreads to the vagus nerve. Ingested toxins and alterations in gut microbiota can induce α-synuclein aggregation and PD, however, it is not known how PD starts. Recently, it has been shown that sensory cells of the gut known as enteroendocrine cells (EECs) contain α-synuclein and synapse with enteric nerves, thus providing a connection from the gut to the brain. It is possible that abnormal α-synuclein first develops in EECs and spreads to the nervous system.

Keywords: Alpha-synuclein; Enteroendocrine cell; Gastrointestinal tract; Lewy body; Parkinson’s disease; Prion.

FIGURE 1. Pathological progression of α-synuclein

Adverse conditions induce changes in the shape of α-synuclein that can serve as a template for misfolding of other molecules. Seeded aggregation leads formation of oligomers and fibrils that comprise Lewy bodies. [Adapted from (Goedert, 2015)].

FIGURE 2. α-synuclein is expressed in enteroendocrine cells

Immunohistological staining of a CCK type EEC cell (green) is shown to contain α-synuclein (red). Below the basal surface of the EEC are other α-synuclein-containing cells. [Reproduced from (Chandra et al., 2017)].