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01.12.2018 | Research article | Ausgabe 1/2018 Open Access

Molecular Neurodegeneration 1/2018

Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve

Zeitschrift:
Molecular Neurodegeneration > Ausgabe 1/2018
Autoren:
Norihito Uemura, Hisashi Yagi, Maiko T. Uemura, Yusuke Hatanaka, Hodaka Yamakado, Ryosuke Takahashi
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13024-018-0257-5) contains supplementary material, which is available to authorized users.
A correction to this article is available online at https://​doi.​org/​10.​1186/​s13024-019-0331-7.

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.
Zusatzmaterial
Additional file 1: Figure S1. Phosphorylated α-synuclein (p-α-Syn) pathology in the stomach 45 days after α-Syn preformed fibrils were inoculated into a mouse gastric wall. a P-α-Syn (EP1536Y) immunohistochemistry of the serial section from Fig. 1d. No apparent p-α-Syn pathology is seen. Scale bar 100 μm. b P-α-Syn (EP1536Y) immunohistochemistry of the serial section from Fig. 1g. No apparent p-α-Syn pathology is seen in the myenteric neurons. Scale bar 100 μm. c P-α-Syn (EP1536Y) immunohistochemistry of another section showing p-α-Syn aggregates in the myenteric plexus (arrow), enlarged in the inset. Scale bar 20 μm. (TIF 4963 kb)
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