Tau accumulates in Crohn's disease gut

Abstract

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.

Tau in the gut, does it really matter?

“…As far as we are aware, no sarkosyl extraction experiments have been performed in the handful of studies that have analysed tau expression in the gut of AD, PSP and CBD subjects (Dugger et al ,2016(Dugger et al , , 2019Lionnet et al 2018;Shankle et al 1993). Regarding enteric neuropathies, we were unable to detect any sarkosyl-insoluble tau in the GI tract samples from Crohn's disease cases, despite the fact that tau is up-regulated in Crohn's disease gut (Prigent et al 2020). We believe that the identification of potential pathological tau species in the gut would greatly benefit from the recently developed ultrasensitive amplification techniques such as protein misfolding cyclic amplification or real-time quaking-induced conversion (Kraus et al 2019;Meyer et al 2014).…”

“…These similarities between the ENS and CNS suggest that a disease process affecting the CNS, especially a neurodegenerative disorder, could also involve its enteric counterpart. In support of this, alpha-synuclein deposits, the pathological hallmark of Parkinson's disease, are not only found in the brain but also in the gut in almost all Parkinsonian patients (Beach et al 2010;Gelpi et al 2014;Wakabayashi et al 1988), leading to the concept of enteric synucleinopathy (De Guilhem De Lataillade et al 2020).…”

“…Using biopsies and full-thickness segments of colon, we observed an increased the expression of tau in the submucosal and myenteric plexus in Crohn's disease relative to controls. Additional experiments performed in the primary culture of enteric neurons and nuclear factor erythroid 2-related factor 2 knockout mice showed that the up-regulation of tau was not transcriptionally regulated but instead likely resulted in a decrease in protein clearance via an nuclear factor erythroid 2-related factor 2 pathway (Prigent et al 2020), as already reported for tau in the CNS (Jo et al 2014). In sharp contrast to tau, the expression of synapsin I, a neuronal phosphoprotein associated with the cytoplasmic surface of synaptic vesicles, was significantly decreased in Crohn's disease colon (Prigent et al 2019), further reinforcing previous observations that showed axonal necrosis and synaptic loss in Crohn's disease gut (Dvorak et al 1993).…”

“…The phosphorylation of tau at multiple serine and threonine sites has been described in both developing and adult brain and is the predominant mechanism by which tau binding and stabilizing of microtubules is regulated (reviewed in (Guo et al 2017)). Tau from the human adult colon is also physiologically phosphorylated at various serine and threonine residues including serines 202, 231, 396, 404 and threonine 205 (numbering according to the longest human tau isoform) (Dugger et al ,2016(Dugger et al , , 2019Lionnet et al 2018;Prigent et al 2020) (Figure 2); phosphorylation at serines 202, 262 and threonines 181 and 205 has also been reported in the colonic myenteric plexus of rodents (Chiocchetti et al 2021;Pellegrini et al 2020;Phillips et al 2009). Soluble tau from the non-diseased adult human brain consists of a heterogeneous mixture of tau isoforms in multiple states of phosphorylation (Biernat et al 1992;Goedert et al 1992) and dephosphorylation of brain lysates induces a downwards shift enabling a more precise identification of the six tau isoforms by SDS-PAGE (Hanger et al 2002).…”

“…tau phosphorylated at serine 202/threonine 205 and serine 396/404 detected by AT8 and PHF-1 respectively) are pathological within the brain but not within the ENS. They also suggest that, unlike alphasynuclein in Parkinson's disease (Volpicelli-Daley & Brundin, 2018;De Guilhem De Lataillade et al 2020), tau may not have a marked propensity to propagate into or from the periphery at least not via the gut, and that the pathological process in PSP and AD is limited to the CNS and does not involve the ENS (Wakabayashi et al 2010).…”