Parkinson's disease from the gut

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 alpha-synuclein. Misfolding of alpha-synuclein confers prion-like properties enabling its spread from cell to cell. Misfolded alpha-synuclein also serves as a template and induces misfolding of endogenous alpha-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 alpha-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 alpha-synuclein appear in enteric nerves before they appear in the brain and injection of abnormal alpha-synuclein into the wall of the intestine spreads to the vagus nerve. Ingested toxins and alterations in gut microbiota can induce asynuclein 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 alpha-synuclein and synapse with enteric nerves, thus providing a connection from the gut to the brain. It is possible that abnormal alpha-synuclein first develops in EECs and spreads to the nervous system. Published by Elsevier B.V.