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α-Synuclein in gut endocrine cells and its implications for Parkinson’s disease
Rashmi Chandra, … , Robert L. Nussbaum, Rodger A. Liddle
Rashmi Chandra, … , Robert L. Nussbaum, Rodger A. Liddle
Published June 15, 2017
Citation Information: JCI Insight. 2017;2(12):e92295. https://doi.org/10.1172/jci.insight.92295.
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Research Article Gastroenterology Neuroscience

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

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Abstract

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 α-synuclein known as Lewy bodies. Although the cause of sporadic PD is not well understood, abundant clinical and pathological evidence show that misfolded α-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 α-synuclein initiates misfolding of native α-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 α-synuclein is expressed in the EEC line, STC-1, and native EECs of mouse and human intestine. Furthermore, α-synuclein–containing EECs directly connect to α-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 α-synuclein folding in the EECs, thereby beginning a process by which misfolded α-synuclein could propagate from the gut epithelium to the brain.

Authors

Rashmi Chandra, Annie Hiniker, Yien-Ming Kuo, Robert L. Nussbaum, Rodger A. Liddle

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Figure 1

α-Synuclein protein is expressed in STC-1 cells.

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α-Synuclein protein is expressed in STC-1 cells.
(A) Relative quantitati...
(A) Relative quantitation of Gapdh, α-synuclein (Snca), cholecystokinin (Cck), and peptide YY (Pyy) mRNAs in STC-1 and SH-SY5Y cells showing that α-synuclein mRNA is present in STC-1 cells. β-Actin (Actb) was used as the normalizer, and RNA isolated from HeLa cells served as a comparator. Data represent mean ± SEM of 3 individual experiments. (B) Coomassie Blue–stained 4%–12% gradient SDS-PAGE gel and corresponding immunoblot of STC-1 cells, A53T mouse brain, and Snca-/- mouse brain extracts with α-synuclein monoclonal antibody. A nonspecific band (asterisk) was detected in A53T and Snca-/- mouse brain extracts. The molecular weights of protein bands present in the ladder are indicated in kDa. (C) 3D Z-stack image of STC-1 cells showing α-synuclein (red) in the cytoplasm. Cytoskeletal staining is shown with β-tubulin (green). Scale bar: 20 μm.

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