Cited by 925Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNuclear Receptors and Signaling

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Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats

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Holmqvist, Staffan, Chutna, Oldriska, Bousset, Luc, Aldrin-Kirk, Patrick, Li, Wen, Björklund, Tomas, Wang, Zhan-You, Roybon, Laurent, Melki, Ronald, Li, Jia-Yi·2014·Acta Neuropathologica

DOI 10.1007/s00401-014-1343-6

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Abstract

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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Reply
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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: Holmqvist, Staffan
Bousset, Luc
Aldrin-Kirk, Patrick
Li, Wen
Björklund, Tomas
Wang, Zhan-You
Roybon, Laurent
Melki, Ronald
Venue: Acta Neuropathologica
Publisher: Springer Science and Business Media LLC
Published: 2014-10-09
Volume: 128
Issue: 6
Pages: 805-820
ISSN: 0001-6322 (ISSN-L)
1432-0533
DOI: 10.1007/s00401-014-1343-6
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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Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats

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