Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections

Ulusoy, Ayşe; Phillips, Robert; Helwig, Michael; Klinkenberg, Michael; Powley, Terry L.; Monte, Donato A. Di

doi:10.1007/s00401-016-1661-y

Cited by 157 publications

(112 citation statements)

References 29 publications

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“…In fact, earlier work by El Agnaf and colleagues had demonstrated the presence of extracellular α-syn in human plasma and cerebrospinal fluid, thus α-syn could conceivably enter cells from extracellular space (El-Agnaf et al 2003). These results and many subsequent in vivo studies gave support to the prion-like hypothesis of α-syn transfer from cell to cell (Table 1) (Desplats et al 2009; Kordower et al 2011; Luk et al 2012b; Mougenot et al 2012; Luk et al 2012a; Ulusoy et al 2013; Recasens et al 2014; Holmqvist et al 2014; Peelaerts et al 2015; Paumier et al 2015; Helwig et al 2016; Koller et al 2017; Ulusoy et al 2017; Abdelmotilib et al 2017). …”

Section: Introductionsupporting

confidence: 67%

“…Sargent and colleagues also used M83 transgenic mice in combination with intracerebral or systemic (intraperitoneal) injection of brain homogenates from sick mice to demonstrate that the type of inoculum and the genotype (hemizygous vs. homozygous) of the mouse determine the pathology load (phosphorylated α-syn) in the brain (Sargent et al 2017). Finally, Ulusoy and colleagues performed injections of adeno-associated virus (AAV) 2/6 expressing human α-syn into rat midbrain, which led to the presence of human α-syn in vagal motor neurons and in gastric nerve endings of visceromotor vagal projections (Ulusoy et al 2017). Taken together, all these results suggest that the dorsal motor nucleus of the vagal nerve could be critical in inducing development of pathology in rostral locations of the brain.…”

Section: With Respect To the Connectome Is There A Difference In Promentioning

confidence: 99%

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The concept of alpha-synuclein as a prion-like protein: ten years after

2018

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Parkinson's disease is characterized by the loss of nigrostriatal dopaminergic signaling and the presence of alpha-synuclein aggregates (also called Lewy bodies and neurites) throughout the brain. In 2003, Braak and colleagues created a staging system for Parkinson's disease describing the connection between the alpha-synuclein pathology and disease severity. Later, they suggested that the pathology might initially be triggered by exogenous insults _targeting the gut and olfactory system. In 2008, we and other groups documented Lewy pathology in grafted neurons in people with Parkinson's disease who had been transplanted over a decade prior to autopsy. We proposed that the Lewy pathology in the grafted neurons was the result of permissive templating or prion-like spread of alpha-synuclein pathology from neurons in the host to those in the grafts. During the following ten years, several studies described the transmission of alpha-synuclein pathology between neurons, both in cell culture and in experimental animals. Recent research has also begun to identify underlying molecular mechanisms. Collectively, these experimental studies tentatively support the idea that the progression from one Braak stage to the next is the consequence of prion-like propagation of Lewy pathology. However, definitive proof that intercellular propagation of alpha-synuclein pathology occurs in Parkinson's disease cases has proven difficult to secure. In this review, we highlight several open questions that currently prevent us from concluding with certainty that prion-like transfer of alpha-synuclein contributes to the progression of Parkinson's disease.

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Section: Introductionsupporting

confidence: 67%

Section: With Respect To the Connectome Is There A Difference In Promentioning

confidence: 99%

The concept of alpha-synuclein as a prion-like protein: ten years after

2018

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“…Also, a decreasing density of asyn pathology in the myenteric plexus from the stomach to the transverse colon would suggest that the pathology was derived from DMV motor efferents, which are known to exhibit this pattern of innervation [7]. Of note, the majority of asyn-positive synapses in the rat myenteric plexus are DMV motor efferents, whereas sensory vagal afferents are asyn-negative and local enteric neurons express asyn at much lower frequencies [37, 46, 47, 54]. Thus, the DMV motor efferents could be a particular vulnerable system for asyn pathology and propagation.…”

Section: Discussionmentioning

confidence: 99%

“…However, the vast majority of previous animal studies employed intracerebral inoculation with asyn seeds, which cannot inform the dual-hit hypothesis (reviewed in [15, 49]). It has been shown that asyn aggregates can be transported retrogradely and anterogradely through the vagus [19, 53, 54]. A seminal study by Holmqvist et al demonstrated that the preformed asyn fibrils (PFF) injected into the duodenum wall of wild-type rats were transported to the DMV within 6 days [19].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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The conversion of endogenous alpha-synuclein (asyn) to pathological asyn-enriched aggregates is a hallmark of Parkinson’s disease (PD). These inclusions can be detected in the central and enteric nervous system (ENS). Moreover, gastrointestinal symptoms can appear up to 20 years before the diagnosis of PD. The dual-hit hypothesis posits that pathological asyn aggregation starts in the ENS, and retrogradely spreads to the brain. In this study, we tested this hypothesis by directly injecting preformed asyn fibrils into the duodenum wall of wild-type rats and transgenic rats with excess levels of human asyn. We provide a meticulous characterization of the bacterial artificial chromosome (BAC) transgenic rat model with respect to initial propagation of pathological asyn along the parasympathetic and sympathetic pathways to the brainstem, by performing immunohistochemistry at early time points post-injection. Induced pathology was observed in all key structures along the sympathetic and parasympathetic pathways (ENS, autonomic ganglia, intermediolateral nucleus of the spinal cord (IML), heart, dorsal motor nucleus of the vagus, and locus coeruleus (LC)) and persisted for at least 4 months post-injection. In contrast, asyn propagation was not detected in wild-type rats, nor in vehicle-injected BAC rats. The presence of pathology in the IML, LC, and heart indicate trans-synaptic spread of the pathology. Additionally, the observed asyn inclusions in the stomach and heart may indicate secondary anterograde propagation after initial retrograde spreading. In summary, trans-synaptic propagation of asyn in the BAC rat model is fully compatible with the “body-first hypothesis” of PD etiopathogenesis. To our knowledge, this is the first animal model evidence of asyn propagation to the heart, and the first indication of bidirectional asyn propagation via the vagus nerve, i.e., duodenum-to-brainstem-to-stomach. The BAC rat model could be very valuable for detailed mechanistic studies of the dual-hit hypothesis, and for studies of disease modifying therapies _targeting early pathology in the gastrointestinal tract.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-02040-w) contains supplementary material, which is available to authorized users.

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“…It has also recently been demonstrated that α‐synuclein pathology can spread to involve multiple brain regions including the SNc after injection of PFFs into the submucosal region of the stomach of transgenic mice or the olfactory bulb of wild‐type mice, consistent with the notion of prion‐like spread. Interestingly, spread from the CNS to the gastrointestinal (GI) tract has also been described following gene delivery of α‐synuclein into the vagus nerve of wild‐type mice …”

Section: Introductionmentioning

confidence: 99%