Abstract

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

Highlights

  • 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)

  • Since Lewy pathology is found in the enteric nervous system (ENS) in the early stage of PD, they hypothesized that Lewy pathology in the ENS travels retrogradely to the dorsal motor nucleus of the vagus nerve (dmX) and proceeds from there in a caudo-rostral direction [8]

  • The experimental conditions differ from the putative progression of Lewy pathology from the ENS to the dmX in human PD, we demonstrated that misfolded fibrillar forms of α-Syn present in the gastric wall were capable of inducing LBlike pathology in the dmX via the vagus nerve

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Summary

Introduction

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 travels retrogradely to the dorsal motor nucleus of the vagus nerve (dmX), proceeding from there in a caudo-rostral direction. Braak et al integrated these observations into a staging system for PD consisting of six stages, each defined by Lewy pathology found in particular neuroanatomical structures This staging system has gained much attention because it seems to explain the clinical course of PD well, from prodromal symptoms appearing early, to motor symptoms in the middle stage, and to cognitive dysfunction in the late stage [3]

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