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.

Epidemiological Evidence for an Immune Component of Parkinson’s Disease

“…Intracellular alpha-synuclein staining in infiltrating monocytic cells from colonic biopsies of UC and CD patients was also described in a small study [21]. The co-occurrence of alpha-synuclein and tau deposits has been described in PD [22] and further supporting pathophysiological links between PD and CD, upregulation of two main human tau isoforms has been shown in the ENS of CD patients [23]. The relationship may be genetically mediated; as discussed above, there is evidence of genetic overlap between CD and PD, both from GWAS, as well as data from LRRK2 cohort studies [8,24].…”

Tau in the gut, does it really matter?

“…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).…”

“…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.…”

“…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.…”

Immunogenetic Determinants of Parkinson’s Disease Etiology

“…Additional candidate shared genes between PD and CD have recently come to attention. There are hints that both alpha-synuclein and tau proteins, encoded by the SNCA and MAPT genes respectively, and considered pathological hallmarks in PD, may also be involved in CD: increased expression levels of alphasynuclein protein were detected in inflamed tissues of CD patients [110] and tau protein expression was found upregulated in the enteric nervous system in CD patients [111]. However, these studies were carried out at a protein level and do not provide enough evidence to assess genetic comorbidity.…”