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Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats
Open accessAbstract
The cellular hallmarks of Parkinson's disease (PD) are the loss of nigral dopaminergic neurons and the formation of α-synuclein-enriched Lewy bodies and Lewy neurites in the remaining neurons. Based on the topographic distribution of Lewy bodies established after autopsy of brains from PD patients, Braak and coworkers hypothesized that Lewy pathology primes in the enteric nervous system and spreads to the brain, suggesting an active retrograde transport of α-synuclein (the key protein component in Lewy bodies), via the vagal nerve. This hypothesis, however, has not been tested experimentally thus far. Here, we use a human PD brain lysate containing different forms of α-synuclein (monomeric, oligomeric and fibrillar), and recombinant α-synuclein in an in vivo animal model to test this hypothesis. We demonstrate that α-synuclein present in the human PD brain lysate and distinct recombinant α-synuclein forms are transported via the vagal nerve and reach the dorsal motor nucleus of the vagus in the brainstem in a time-dependent manner after injection into the intestinal wall. Using live cell imaging in a differentiated neuroblastoma cell line, we determine that both slow and fast components of axonal transport are involved in the transport of aggregated α-synuclein. In conclusion, we here provide the first experimental evidence that different α-synuclein forms can propagate from the gut to the brain, and that microtubule-associated transport is involved in the translocation of aggregated α-synuclein in neurons.
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“Third, cellular and animal studies have provided a model for prion-like spread of α-synuclein from the gut to the brain via the enteric nervous system, chiefly through the vagus nerve [15–17].”
From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [17]
In the citing paper
“Involvement of the vagal nerve in the propagation of α-synuclein from the gut to the brain was demonstrated by Holmqvist et al. [399].”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [399]
In the citing paper
“In accordance with this hypothesis it has been shown that alphasynuclein can be retrogradely transported from the intestinal wall to the brain in rats (Holmqvist et al., 2014).”
From The Gut-Brain Axis in Parkinson’s Disease: Possibilities for Food-Based Therapies (2017) · cites this paper as Holmqvist et al., 2014
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“In accordance with this hypothesis it has been shown that alphasynuclein can be retrogradely transported from the intestinal wall to the brain in rats (Holmqvist et al., 2014).”
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Metadata
- Authors
- Holmqvist, S., Chutna, O., Bousset, L., Aldrin-Kirk, P., Li, W., Björklund, T., Wang, Z.-Y., Roybon, L., Melki, R., & Li, J.-Y.
- Affiliations
- Lund University (SE)
- Centre National de la Recherche Scientifique (FR)
- Northeastern University (CN)
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2014-10-09
- Volume
- 128
- Issue
- 6
- Pages
- 805-820
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W1995281235
- Cited by
- 925
- References
- 51
- Citations by year
- 2026: 47 · 2025: 67 · 2024: 73 · 2023: 67 · 2022: 110 · 2021: 132 · 2020: 102 · 2019: 107 · 2018: 75 · 2017: 59 · 2016: 43 · 2015: 38 · 2014: 3
- FWCI
- 30.94
- Type
- journal article
- Language
- en
- Open access
- green
- lup.lub.lu.se
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Funders
- Agence Nationale de la Recherche (ANR-11-BSV8-0021)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, alpha-synuclein, Lewy bodies, gut-brain axis, vagus nerve, retrograde transport, enteric nervous system, dorsal motor nucleus of the vagus, axonal transport, alpha-synuclein aggregation, rat model
- MeSH terms
- Animals, Axonal Transport, Brain, Disease Models, Animal, Humans, Parkinson Disease, Recombinant Proteins, Vagus Nerve, Rats, Sprague-Dawley, Disease Progression, Gastrointestinal Tract, Cell Line, Tumor, alpha-Synuclein
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