α‐Synuclein expression is induced by depolarization and cyclic AMP in enteric neurons

Paillusson, Sébastien; Tasselli, Maddalena; Lebouvier, Thibaud; Mahé, Maxime Michaël; Chevalier, J.; Biraud, Mandy; Cario‐Toumaniantz, Chrystelle; Neunlist, Michel; Derkinderen, Pascal

doi:10.1111/j.1471-4159.2010.06962.x

Cited by 27 publications

(27 citation statements)

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“…In the latter case, a signaling pathway involving ERK/PI3 kinase signaling mediated ZSCAN-induced SNCA transcriptional activation (Clough and Stefanis 2007;Clough et al 2009). A similar ERK-dependent signaling pathway regulating SNCA production was apparent in enteric neurons (Paillusson et al 2010). Methylation may be important in SNCA expression, as methylation within Intron 1 suppressed SNCA transcriptional activity, and brains of patients with LB diseases showed decreased methylation within this region, suggesting epigenetic regulation of SNCA expression (Jowaed et al 2010;Matsumoto et al 2010).…”

Section: Gain-of-function and Accumulation Of A-synucleinmentioning

confidence: 81%

-Synuclein in Parkinson's Disease

Stefanis¹

2011

Cold Spring Harbor Perspectives in Medicine

1,146

732

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Section: Gain-of-function and Accumulation Of A-synucleinmentioning

confidence: 81%

-Synuclein in Parkinson's Disease

Stefanis¹

2011

Cold Spring Harbor Perspectives in Medicine

1,146

732

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“…In a more general consideration, ERK is known to be activated in response to stimuli linked to neuronal activity [43]. However, it is also well known that the activation of MAPK is transient [43,44] and hardly ever sustained in physiological conditions, due to desensitizing or negative feedback processes.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is also well known that the activation of MAPK is transient [43,44] and hardly ever sustained in physiological conditions, due to desensitizing or negative feedback processes. We could assume that ENS activation precociously activates ERK pathways that might not be further impacted by LPS stimulation.…”

Section: Discussionmentioning

confidence: 99%

Modulation of lipopolysaccharide-induced neuronal response by activation of the enteric nervous system

Coquenlorge

Duchalais

Chevalier

et al. 2014

J Neuroinflammation

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BackgroundEvidence continues to mount concerning the importance of the enteric nervous system (ENS) in controlling numerous intestinal functions in addition to motility and epithelial functions. Nevertheless, little is known concerning the direct participation of the ENS in the inflammatory response of the gut during infectious or inflammatory insults. In the present study we analyzed the ENS response to bacterial lipopolysaccharide, in particular the production of a major proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α).MethodsTNF-α expression (measured by qPCR, quantitative Polymerase Chain Reaction) and production (measured by ELISA) were measured in human longitudinal muscle-myenteric plexus (LMMP) and rat ENS primary cultures (rENSpc). They were either treated or not treated with lipopolysaccharide (LPS) in the presence or not of electrical field stimulation (EFS). Activation of extracellular signal-regulated kinase (ERK) and 5’-adenosine monophosphate-activated protein kinase (AMPK) pathways was analyzed by immunocytochemistry and Western blot analysis. Their implications were studied using specific inhibitors (U0126, mitogen-activated protein kinase kinase, MEK, inhibitor and C compound, AMPK inhibitor). We also analyzed toll-like receptor 2 (TLR2) expression and interleukin-6 (IL-6) production after LPS treatment simultaneously with EFS or TNF-α-neutralizing antibody.ResultsTreatment of human LMMP or rENSpc with LPS induced an increase in TNF-α production. Activation of the ENS by EFS significantly inhibited TNF-α production. This regulation occurred at the transcriptional level. Signaling analyses showed that LPS induced activation of ERK but not AMPK, which was constitutively activated in rENSpc neurons. Both U0126 and C compound almost completely prevented LPS-induced TNF-α production. In the presence of LPS, EFS inhibited the ERK and AMPK pathways. In addition, we demonstrated using TNF-α-neutralizing antibody that LPS-induced TNF-α production increased TLR2 expression and reduced IL-6 production.ConclusionsOur results show that LPS induced TNF-α production by enteric neurons through activation of the canonical ERK pathway and also in an AMPK-dependent manner. ENS activation through the inhibition of these pathways decreased TNF-α production, thereby modulating the inflammatory response induced by endotoxin.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0202-7) contains supplementary material, which is available to authorized users.

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“…The mechanism by which environmental agents induce α-synuclein aggregation is unknown. However, a recent study showed that α-synuclein expression in the ENS could be upregulated by agents that cause depolarization and increase the levels of cyclic AMP [24]. …”

Section: Discussionmentioning

confidence: 99%

Transmission of Synucleinopathies in the Enteric Nervous System of A53T Alpha-Synuclein Transgenic Mice

et al. 2011

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Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by abnormal deposition of α-synuclein aggregates in many regions of the central and peripheral nervous systems. Accumulating evidence suggests that the α-synuclein pathology initiates in a few discrete regions and spreads to larger areas in the nervous system. Recent pathological studies of PD patients have raised the possibility that the enteric nervous system is one of the initial sites of α-synuclein aggregation and propagation. Here, we evaluated the induction and propagation of α-synuclein aggregates in the enteric nervous system of the A53T α-synuclein transgenic mice after injection of human brain tissue extracts into the gastric walls of the mice. Western analysis of the brain extracts showed that the DLB extract contained detergent-stable α-synuclein aggregates, but the normal brain extract did not. Injection of the DLB extract resulted in an increased deposition of α-synuclein in the myenteric neurons, in which α-synuclein formed punctate aggregates over time up to 4 months. In these mice, inflammatory responses were increased transiently at early time points. None of these changes were observed in the A53T mice injected with saline or the normal brain extract, nor were these found in the wild type mice injected with the DLB extract. These results demonstrate that pathological α-synuclein aggregates present in the brain of DLB patient can induce the aggregation of endogenous α-synuclein in the myenteric neurons in A53T mice, suggesting the transmission of synucleinopathy lesions in the enteric nervous system.

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α‐Synuclein expression is induced by depolarization and cyclic AMP in enteric neurons

Cited by 27 publications

References 48 publications

-Synuclein in Parkinson's Disease

-Synuclein in Parkinson's Disease

Modulation of lipopolysaccharide-induced neuronal response by activation of the enteric nervous system

Transmission of Synucleinopathies in the Enteric Nervous System of A53T Alpha-Synuclein Transgenic Mice

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