Cited by 237Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingNeuroinflammation and Neurodegeneration Mechanisms

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

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Chandra, Rashmi, Hiniker, Annie, Kuo, Yien-Ming, Nussbaum, Robert L., Liddle, Rodger A.·2017·JCI Insight

DOI 10.1172/jci.insight.92295PMC PMC5470880

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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.

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Authors: Chandra, R., Hiniker, A., Kuo, Y.-M., Nussbaum, R. L., & Liddle, R. A.
Affiliations: Duke University (US)
Department of Pathology and
University of California, San Francisco (US)
ORCID: Chandra, Rashmi
Hiniker, Annie
Kuo, Yien-Ming
Nussbaum, Robert L.
Liddle, Rodger A.
Venue: JCI Insight
Publisher: American Society for Clinical Investigation
Published: 2017-06-15
Volume: 2
Issue: 12
ISSN: 2379-3708 (ISSN-L)
DOI: 10.1172/jci.insight.92295
PMC: PMC5470880
OpenAlex: W2626849072
Cited by: 236
References: 67
Citations by year: 2026: 22 · 2025: 26 · 2024: 28 · 2023: 26 · 2022: 43 · 2021: 28 · 2020: 15 · 2019: 20 · 2018: 23 · 2017: 4
FWCI: 12.00
Type: journal article
Language: en
Open access: gold
doi.org
Locations: JCI Insight (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Veterans Affairs (BX002230, I01 BX002230)
Sandler Foundation
National Institutes of Health (UL1TR001117)
University of California, San Francisco
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK098796, R01DK109368)
National Institute of Neurological Disorders and Stroke (K08NS090633)
Duke Cancer Institute
Topics: Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: alpha-synuclein, Parkinson's disease, enteroendocrine cells, gut-brain axis, Lewy bodies, prion-like propagation, enteric nerves, STC-1 cells, neurodegeneration, intestinal epithelium

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

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