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

Abstract

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.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0257-5) contains supplementary material, which is available to authorized users.

Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

“…The present finding of robust and extensive gut-to-brain asyn propagation contrasts with two recent reports [25, 52]. In those studies, asyn PFFs were injected directly into the stomach or colon of mice, rats, and macaques, but little or no persisting asyn pathology was seen in the brainstem.…”

“…Of note, we did not see asyn pathology in the myenteric and submucosal plexus of the PFF-injected WT rats, which contrasts with the observed persistent enteric pathology in PFF-injected WT rodents and non-human primates [25, 52]. The absence of pathology in the present WT rats could be explained by a species barrier, since we used human asyn PFFs in the WT rats, whereas the previous studies used species-compatible PFFs.…”

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

“…After 12 months, pS129‐positive inclusions were detected throughout the brain in connected areas, including the SNpc. However, there was no further progression of Lewy body‐like pathology at 23 months when pS129 was propagation studied after injecting PFFs into the mouse gastric wall (Rey et al., ; Uemura et al., ). The study demonstrated formation of pS129‐positive aggregates in the dorsal motor nucleus of the vagus nerve, which could be prevented by vagotomy.…”

Spreading of alpha‐synuclein – relevant or epiphenomenon?

“…PD-like pathology has been observed in peripheral neurons at many anatomically distinct sites including the colon (Lebouvier et al 2010) and vermiform appendix (Killinger et al 2018). From these sites, peripheral pathology could then spread to the DMNV through vagus nerve afferents and efferents, effectively seeding the pathological process of PD (Holmqvist et al 2014;Uemura et al 2018). However, results from several studies suggest that the progressive spread of pathology from the peripheral sites to higher brain structures is either rare or unlikely (Holmqvist et al 2014;Uemura et al 2018).…”

“…However, results from several studies suggest that the progressive spread of pathology from the peripheral sites to higher brain structures is either rare or unlikely (Holmqvist et al 2014;Uemura et al 2018). Peripherally injected PFFs into the mouse gastric wall results in pathology in the DMNV (Holmqvist et al 2014;Uemura et al 2018) but this pathology doesn't progressively spread through the CNS Peripheral asyn seeds can accelarate widespread CNS pathology in transgenic mice harboring a aggregation prone pathological variant of a-syn (Sacino et al 2014a). a-Syn aggregates injected into peripheral sites are most likely transported intracellularly to the brain via axonal transport (Freundt et al 2012;Holmqvist et al 2014;Sacino et al 2014a).…”