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α-Synuclein in gut endocrine cells and its implications for Parkinson’s disease
Open accessAbstract
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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“Both cell types naturally express α-synuclein and offer a theoretical source for early pathological α-synuclein aggregation and spread to the brain via the vagus nerve [9, 137].”
From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [137]
In the citing paper
“Gastrointestinal enteroendocrine cells that connect directly to the gut lumen and local neurones, and submucosal neurones which synapse micrometers from the gut lumen, could also be sources of α-synuclein [137].”
From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [137]
In the citing paper
“Both cell types naturally express α-synuclein and offer a theoretical source for early pathological α-synuclein aggregation and spread to the brain via the vagus nerve [9, 137].”
From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [137]
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Castegna, A., Laera, L., Moda, P., Miglietta, S., D’Agostino, M., Ruggiero, M., Cianciulli, A., Filannino, F. M., Porro, C., Butterfield, D. A., et al. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-08102-4 · Cited by 3
Brain-first and body-first subtypes of Lewy body disease
Borghammer, P., Berge, N. V. D., Berg, D., Takahashi, R., Postuma, R. B., & Horsager, J. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-026-01241-8 · Cited by 3
Ernesto, J. T., Damásio, C. M., Gontijo, V. S., Gasparotto, J., & Viegas, C. (2023) · Exploration of Neuroprotective Therapy · doi:10.37349/ent.2023.00038 · Cited by 2
Muronetz, V. I., Kurochkina, L. P., Leisi, E. V., & Kudryavtseva, S. S. (2023) · Microbiology Research · doi:10.3390/microbiolres14040131 · Cited by 3
Microbiota and cognitive impairment: Current challenges and future perspectives
Chapelet, G., Noble, W. J., & Derkinderen, P. (2024) · Journal of Alzheimer s Disease · doi:10.1177/13872877241289057 · Cited by 2
Role of the Gut Microbiome and Bacterial Amyloids in the Development of Synucleinopathies
Trubitsina, N. P., Matiiv, A. B., Rogoza, T. M., Zudilova, A. A., Bezgina, M. D., Zhouravleva, G. A., & Bondarev, S. A. (2024) · Biochemistry (Moscow) · doi:10.1134/s0006297924030118 · Cited by 2
Akkermansia muciniphila secretome promotes α-synuclein aggregation in enteroendocrine cellsPreprint
Neto, D. P. A., Bosque, B. P., de Godoy, J. V. P., Rodrigues, P. V., Meneses, D. D., Tostes, K., Tonoli, C. C. C., González-Billault, C. E., & Fonseca, M. D. C. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.12.430931 · Cited by 2
de Ora, L. O., Uyeda, K. S., & Bess, E. N. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.06.08.495350 · Cited by 2
Intestinal enteroendocrine cell subtype differentiation and hormone production in zebrafishPreprint
Morash, M., Kay, R. G., Soderblom, E. J., MacLean, G. H., Wen, J., Moore, P. J., Lickwar, C. R., Gribble, F. M., Reimann, F. M., Liddle, R. A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.17.633579 · Cited by 2
Self-citationForged in O2: Transition metal ions and the rise of aerobic life
Uyeda, K. S., & Borovik, A. S. (2025) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2025.113147 · Cited by 1
Singh, S., Capacio, A., Braun, C. A., Carroll‐Portillo, A., Ryman, S. G., & Lin, H. C. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1672793 · Cited by 1
Neto, D. P. A., Rodrigues, P. V., Sartori, C. R., & Sant’Ana, A. S. (2026) · Fungal Biology Reviews · doi:10.1016/j.fbr.2026.100500 · Cited by 1
Spreading of alpha-synuclein pathology from the gut to the brain in Parkinson's disease
Jevans, B., & Monte, D. A. D. (2021) · International review of movement disorders · doi:10.1016/bs.irmvd.2021.08.004 · Cited by 1
Research progress in rapid eye movement sleep behavior disorder.
Peng, X., & Zhang, H. (2021) · PubMed Central · doi:10.11817/j.issn.1672-7347.2021.200928 · Cited by 1
Circulating Extracellular Vesicles as a Potential Mediator of Synuclein Pathology in the Gut
Sampson, T. R. (2024) · Movement Disorders · doi:10.1002/mds.29673 · Cited by 1
Metadata
- 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)
- Venue
- JCI Insight
- Published
- 2017-06-15
- Volume
- 2
- Issue
- 12
- ISSN
- 2379-3708 (ISSN-L)
- 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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