a-Synuclein in gut endocrine cells and its implications for Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease with devastating clinical manifestations. In PD, neuronal death is associated with intracellular aggregates of the neuronal protein a-synuclein known as Lewy bodies. Although the cause of sporadic PD is not well understood, abundant clinical and pathological evidence show that misfolded a-synuclein is found in enteric nerves before it appears in the brain. This suggests a model in which PD pathology originates in the gut and spreads to the central nervous system via cell-to-cell prion-like propagation, such that transfer of misfolded a-synuclein initiates misfolding of native a-synuclein in recipient cells. We recently discovered that enteroendocrine cells (EECs), which are part of the gut epithelium and directly face the gut lumen, also possess many neuron-like properties and connect to enteric nerves. In this report, we demonstrate that a-synuclein is expressed in the EEC line, STC-1, and native EECs of mouse and human intestine. Furthermore, a-synuclein–containing EECs directly connect to a-synuclein–containing nerves, forming a neural circuit between the gut and the nervous system in which toxins or other environmental influences in the gut lumen could affect a-synuclein folding in the EECs, thereby beginning a process by which misfolded asynuclein could propagate from the gut epithelium to the brain. Research Article Gastroenterology Neuroscience