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Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve.
Mol Neurodegener. 2018 05 11; 13(1):21.MN

Abstract

BACKGROUND

Intraneuronal α-synuclein (α-Syn) aggregates known as Lewy bodies (LBs) and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are the pathological hallmarks of Parkinson's disease (PD). Braak's hypothesis based on autopsy studies suggests that Lewy pathology initially occurs in the enteric nervous system (ENS) and then travels retrogradely to the dorsal motor nucleus of the vagus nerve (dmX), proceeding from there in a caudo-rostral direction. Recent evidence that α-Syn aggregates propagate between interconnected neurons supports this hypothesis. However, there is no direct evidence demonstrating this transmission from the ENS to the dmX and then to the SNpc.

METHODS

We inoculated α-Syn preformed fibrils (PFFs) or phosphate-buffered saline (PBS) into the mouse gastric wall and analyzed the progression of the pathology.

RESULTS

The mice inoculated with α-Syn PFFs, but not with PBS, developed phosphorylated α-Syn (p-α-Syn)-positive LB-like aggregates in the dmX at 45 days postinoculation. This aggregate formation was completely abolished when vagotomy was performed prior to inoculation of α-Syn PFFs, suggesting that the aggregates in the dmX were retrogradely induced via the vagus nerve. Unexpectedly, the number of neurons containing p-α-Syn-positive aggregates in the dmX decreased over time, and no further caudo-rostral propagation beyond the dmX was observed up to 12 months postinoculation. P-α-Syn-positive aggregates were also present in the myenteric plexus at 12 months postinoculation. However, unlike in patients with PD, there was no cell-type specificity in neurons containing those aggregates in this model.

CONCLUSIONS

These results indicate that α-Syn PFF inoculation into the mouse gastrointestinal tract can induce α-Syn pathology resembling that of very early PD, but other factors are apparently required if further progression of PD pathology is to be replicated in this animal model.

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Authors+Show Affiliations

Uemura N
Department of Neurology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Kyoto, Sakyoku, 606-8507, Japan. nuemura@kuhp.kyoto-u.ac.jp.
Yagi H
Center for Research on Green Sustainable Chemistry, Tottori University, 4-101 Koyamacho-minami, Tottori, Tottori, 680-8550, Japan.
Uemura MT
Department of Neurology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Kyoto, Sakyoku, 606-8507, Japan.
Hatanaka Y
Department of Neurology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Kyoto, Sakyoku, 606-8507, Japan.
Yamakado H
Department of Neurology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Kyoto, Sakyoku, 606-8507, Japan.
Takahashi R
Department of Neurology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Kyoto, Sakyoku, 606-8507, Japan. ryosuket@kuhp.kyoto-u.ac.jp.

MeSH

AnimalsBrain StemGastrointestinal TractLewy BodiesMaleMiceMice, Inbred C57BLParkinson DiseaseProtein TransportVagus Nervealpha-Synuclein

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29751824

Citation

Uemura, Norihito, et al. "Inoculation of Α-synuclein Preformed Fibrils Into the Mouse Gastrointestinal Tract Induces Lewy Body-like Aggregates in the Brainstem Via the Vagus Nerve." Molecular Neurodegeneration, vol. 13, no. 1, 2018, p. 21.
Uemura N, Yagi H, Uemura MT, et al. Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve. Mol Neurodegener. 2018;13(1):21.
Uemura, N., Yagi, H., Uemura, M. T., Hatanaka, Y., Yamakado, H., & Takahashi, R. (2018). Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve. Molecular Neurodegeneration, 13(1), 21. https://doi.org/10.1186/s13024-018-0257-5
Uemura N, et al. Inoculation of Α-synuclein Preformed Fibrils Into the Mouse Gastrointestinal Tract Induces Lewy Body-like Aggregates in the Brainstem Via the Vagus Nerve. Mol Neurodegener. 2018 05 11;13(1):21. PubMed PMID: 29751824.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve. AU - Uemura,Norihito, AU - Yagi,Hisashi, AU - Uemura,Maiko T, AU - Hatanaka,Yusuke, AU - Yamakado,Hodaka, AU - Takahashi,Ryosuke, Y1 - 2018/05/11/ PY - 2018/03/09/received PY - 2018/05/02/accepted PY - 2018/5/13/entrez PY - 2018/5/13/pubmed PY - 2018/11/10/medline KW - Enteric nervous system KW - Lewy bodies KW - Parkinson’s disease KW - Propagation KW - Vagus nerve KW - α-synuclein SP - 21 EP - 21 JF - Molecular neurodegeneration JO - Mol Neurodegener VL - 13 IS - 1 N2 - BACKGROUND: Intraneuronal α-synuclein (α-Syn) aggregates known as Lewy bodies (LBs) and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are the pathological hallmarks of Parkinson's disease (PD). Braak's hypothesis based on autopsy studies suggests that Lewy pathology initially occurs in the enteric nervous system (ENS) and then travels retrogradely to the dorsal motor nucleus of the vagus nerve (dmX), proceeding from there in a caudo-rostral direction. Recent evidence that α-Syn aggregates propagate between interconnected neurons supports this hypothesis. However, there is no direct evidence demonstrating this transmission from the ENS to the dmX and then to the SNpc. METHODS: We inoculated α-Syn preformed fibrils (PFFs) or phosphate-buffered saline (PBS) into the mouse gastric wall and analyzed the progression of the pathology. RESULTS: The mice inoculated with α-Syn PFFs, but not with PBS, developed phosphorylated α-Syn (p-α-Syn)-positive LB-like aggregates in the dmX at 45 days postinoculation. This aggregate formation was completely abolished when vagotomy was performed prior to inoculation of α-Syn PFFs, suggesting that the aggregates in the dmX were retrogradely induced via the vagus nerve. Unexpectedly, the number of neurons containing p-α-Syn-positive aggregates in the dmX decreased over time, and no further caudo-rostral propagation beyond the dmX was observed up to 12 months postinoculation. P-α-Syn-positive aggregates were also present in the myenteric plexus at 12 months postinoculation. However, unlike in patients with PD, there was no cell-type specificity in neurons containing those aggregates in this model. CONCLUSIONS: These results indicate that α-Syn PFF inoculation into the mouse gastrointestinal tract can induce α-Syn pathology resembling that of very early PD, but other factors are apparently required if further progression of PD pathology is to be replicated in this animal model. SN - 1750-1326 UR - https://www.unboundmedicine.com/medline/citation/29751824/Inoculation_of_α_synuclein_preformed_fibrils_into_the_mouse_gastrointestinal_tract_induces_Lewy_body_like_aggregates_in_the_brainstem_via_the_vagus_nerve_ DB - PRIME DP - Unbound Medicine ER -