Acute inflammation down‐regulates alpha‐synuclein expression in enteric neurons

Prigent, Annick; Gonzalès, Jacques; Berre‐Scoul, Catherine Le; Rolli–Derkinderen, Malvyne; Neunlist, Michel; Derkinderen, Pascal

doi:10.1111/jnc.14656

Cited by 25 publications

(23 citation statements)

References 52 publications

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“…Although we identified an elevated amount of alphasynuclein in colonic samples from patients with CD, we were unable to find any pathological changes such as phosphorylation and aggregation known to be associated with PD [43]. In addition, two independent studies performed in both acute and chronic DSS-treated mice found that intestinal inflammation was not associated with any increase in alpha-synuclein expression and phosphorylation [34,44] and we recently showed that alpha-synuclein in enteric neurons was transcriptionally downregulated by acute inflammation via a p38 signaling pathway [44].…”

Section: How Gi Inflammation May Influence the Development Of Pd?mentioning

confidence: 99%

Is Parkinson’s disease a chronic low-grade inflammatory bowel disease?

et al. 2019

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While the pathogenesis of Parkinson's disease is not fully understood, there is increasing evidence that inflammatory responses in the brain are implicated in both disease initiation and progression. The inflammatory process in Parkinson's disease is however not limited to the brain but also involves the gastrointestinal tract. High amounts of cytokines and inflammatory markers are found in the colon of Parkinson's disease patients and there is now strong epidemiological and genetical evidence linking Parkinson's disease to inflammatory bowel diseases. Recent findings obtained in both experimental inflammatory bowel diseases and Parkinson's disease further support a bidirectional link between gastrointestinal inflammation and brain neurodegeneration. Altogether these observations suggest a role for gastrointestinal inflammation in the initiation and progression of Parkinson's disease.

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Section: How Gi Inflammation May Influence the Development Of Pd?mentioning

confidence: 99%

Is Parkinson’s disease a chronic low-grade inflammatory bowel disease?

et al. 2019

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“…The growing body of evidence suggesting that GI inflammation is involved in the development of PD recently led us to investigate the effects of inflammation on alphasynuclein expression in primary culture of rat ENS (23). We showed that two of the proinflammatory cytokines that are elevated in CD ( Figure S1), namely TNF-α and IL-1β, induced a downregulation of alpha-synuclein expression at both mRNA and protein levels in enteric neurons (23). Similar findings were observed when tau mRNA and protein were analyzed (our unpublished results).…”

Section: Discussionmentioning

confidence: 99%

“…Primary cultures of rat ENS were generated and cultured as previously described (23). Cells were treated with 10 µM sulforaphane or MG132 (both from Sigma, Saint-Quentin-Fallavier, France) for 12h.…”

Section: Primary Culture Of Rat Ensmentioning

confidence: 99%

Tau accumulates in Crohn's disease gut

et al. 2020

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A sizeable body of evidence has recently emerged to suggest that gastrointestinal inflammation might be involved in the development of Parkinson's disease. There is now strong epidemiological and genetical evidence linking Parkinson's disease to inflammatory bowel diseases and we recently demonstrated that the neuronal protein alpha-synuclein, which is critically involved in Parkinson's disease pathophysiology, is upregulated in inflamed segments of Crohn's colon. The microtubule associated protein tau is another neuronal protein critically involved in neurodegenerative disorders but, in contrast to alpha-synuclein, no data are available about its expression and phosphorylation patterns in inflammatory bowel diseases. Here, we examined the expression levels of tau isoforms, their phosphorylation profile and truncation in colon biopsy specimens from 16 Crohn's disease and 6 ulcerative colitis patients and compared them to samples from 16 controls. Additional experiments were performed in full thickness segments of colon of 5 Crohn's disease and 5 control subjects, in primary cultures of rat enteric neurons and in Nrf2 knockout mice. Our results show the upregulation of two main human tau isoforms in the enteric nervous system in Crohn's disease but not in ulcerative colitis. This upregulation was not transcriptionally regulated but instead likely resulted from a decrease in protein clearance via an Nrf2 pathway. Our findings, which provide the first detailed characterization of tau in Crohn's disease, suggest that the key proteins involved in neurodegenerative disorders such as alpha-synuclein and tau, might also play a role in Crohn's disease.

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“…Additionally, aSyn expression, but not its pathologic aggregation, is increased in the ENS of patients with Crohn's disease (Prigent et al, 2019b) and inoculation of aSyn fibrils in the GIT is associated with an increased expression of inflammatory mediators in intestinal tissues (Challis et al, 2020). However, by contrast, it was seen that acute inflammatory stress inhibits aSyn expression in primary enteric neurons (Prigent et al, 2019a). Interestingly, inflammatory parameters, pathological aSyn aggregation and motor deficits were demonstrated to be regulated by microbiota in aSyn overexpressing mice (Sampson et al, 2016).…”

Section: Asyn In the Gastro-intestinal System: Pathological Implicationsmentioning

confidence: 99%

Alpha Synuclein Connects the Gut-Brain Axis in Parkinson’s Disease Patients – A View on Clinical Aspects, Cellular Pathology and Analytical Methodology

Schaeffer

Kluge

Böttner

et al. 2020

Front. Cell Dev. Biol.

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Parkinson's disease (PD) is marked by different kinds of pathological features, one hallmark is the aggregation of α-synuclein (aSyn). The development of aSyn pathology in the substantia nigra is associated to the manifestation of motor deficits at the time of diagnosis. However, most of the patients suffer additionally from non-motor symptoms, which may occur already in the prodromal phase of the disease years before PD is diagnosed. Many of these symptoms manifest in the gastrointestinal system (GIT) and some data suggest a potential link to the occurrence of pathological aSyn forms within the GIT. These clinical and pathological findings lead to the idea of a gut-brain route of aSyn pathology in PD. The identification of pathological aSyn in the intestinal system, e.g., by GIT biopsies, is therefore of highest interest for early diagnosis and early intervention in the phase of formation and propagation of aSyn. However, reliable methods to discriminate between physiological and pathological forms of enteral aSyn on the cellular and biochemical level are still missing. Moreover, a better understanding of the physiological function of aSyn within the GIT as well as its structure and pathological aggregation pathways are crucial to understand its role within the enteric nervous system and its spreading from the gut to the brain. In this review, we summarize clinical manifestations of PD in the GIT, and discuss biochemical findings from enteral biopsies. The relevance of pathological aSyn forms, their connection to the gut-brain axis and new developments to identify pathologic forms of aSyn by structural features are critically reviewed.

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Acute inflammation down‐regulates alpha‐synuclein expression in enteric neurons

Cited by 25 publications

References 52 publications

Is Parkinson’s disease a chronic low-grade inflammatory bowel disease?

Is Parkinson’s disease a chronic low-grade inflammatory bowel disease?

Tau accumulates in Crohn's disease gut

Alpha Synuclein Connects the Gut-Brain Axis in Parkinson’s Disease Patients – A View on Clinical Aspects, Cellular Pathology and Analytical Methodology

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