A path for α-synuclein from the gut to the nervous system. Enteroendocrine cells (EECs) express α-synuclein and connect to α-synuclein-containing enteric nerves. This circuit provides a possible route for bacteria or toxins in the gut to induce abnormal α-synuclein formation that could transfer to the nervous system to initiate Parkinson’s disease. Display omitted •Parkinson’s disease is characterized by Lewy bodies in the brain and peripheral nerves.•Misfolding and aggregation of α-synuclein leads to Lewy body formation.•Misfolded α-synuclein can spread in a prion-like fashion.•Epidemiological and experimental evidence suggest PD arises in the gut.•Like neurons, enteroendocrine cells express α-synuclein and could be a source of PD. 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.