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Requirement of cellular prion protein for intestinal barrier function and mislocalization in patients with
Constance S V Petit1, Frédérick Barreau, Laura Besnier
1Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, Paris, France.
Insights
Cellular prion protein (PrP(c)) is crucial for maintaining intestinal barrier integrity by regulating cell-cell junctions. Reduced PrP(c) levels impair this barrier, potentially contributing to inflammatory bowel disease.
Area of Science:
- Gastroenterology
- Cell Biology
- Prion Biology
Background:
- Cellular prion protein (PrP(c)) is a glycoprotein involved in cell adhesion.
- PrP(c) is localized in intestinal epithelial cell-cell junctions and interacts with desmosome proteins.
Purpose of the Study:
- To investigate the role of PrP(c) in maintaining intestinal barrier function.
- To analyze the impact of PrP(c) deficiency on intestinal permeability and intercellular junctions.
Main Methods:
- Analysis of intestinal permeability and intercellular junction structure in PrP(c) knockout mice and wild-type mice.
- PrP(c) knockdown in Caco-2/TC7 enterocytes using small hairpin RNAs.
- Examination of colon samples from patients with inflammatory bowel disease (IBD).
Main Results:
- PrP(c) knockout mice exhibited increased intestinal paracellular permeability and impaired intercellular junctions.
- PrP(c) knockdown in Caco-2/TC7 cells led to increased permeability and reduced transepithelial electrical resistance.
- Decreased levels of key junctional proteins (e.g., E-cadherin, occludin) were observed in PrP(c) deficient cells.
- Reduced PrP(c) levels were found in colonic epithelia of IBD patients.
Conclusions:
- PrP(c) plays a significant role in regulating intestinal epithelial cell-cell junctions and barrier function.
- Altered PrP(c) localization in IBD suggests a link between disrupted barrier function and the disease.
Background & Aims:
Cell adhesion is one function regulated by cellular prion protein (PrP(c)), a ubiquitous, glycosylphosphatidylinositol-anchored glycoprotein. PrP(c) is located in cell-cell junctions and interacts with desmosome proteins in the intestinal epithelium. We investigated its role in intestinal barrier function.
Methods:
We analyzed permeability and structure of cell-cell junctions in intestine tissues from PrP(c) knockout (PrP(c-/-)) and wild-type mice. PrP(c) expression was knocked down in cultured human Caco-2/TC7 enterocytes using small hairpin RNAs. We analyzed colon samples from 24 patients with inflammatory bowel disease (IBD).
Results:
Intestine tissues from PrP(c-/-) mice had greater paracellular permeability than from wild-type mice (105.9 ± 13.4 vs 59.6 ± 10.1 mg/mL fluorescein isothiocyanate-dextran flux; P < .05) and impaired intercellular junctions. PrP(c-/-) mice did not develop spontaneous disease but were more sensitive than wild-type mice to induction of colitis with dextran sulfate (32% mortality vs 4%, respectively; P = .0033). Such barrier defects were observed also in Caco-2/TC7 enterocytes following PrP(c) knockdown; the cells had increased paracellular permeability (1.5-fold over 48 hours; P < .001) and reduced transepithelial electrical resistance (281.1 ± 4.9 vs 370.6 ± 5.7 Ω.cm(2); P < .001). Monolayer shape and cell-cell junctions were altered in cultures of PrP(c) knockdown cells; levels of E-cadherin, desmoplakin, plakoglobin, claudin-4, occludin, zonula occludens 1, and tricellulin were decreased at cell contacts. Cell shape and junctions were restored on PrP(c) re-expression. Levels of PrP(c) were decreased at cell-cell junctions in colonic epithelia from patients with Crohn's disease or ulcerative colitis.
Conclusions:
PrP(c) regulates intestinal epithelial cell-cell junctions and barrier function. Its localization is altered in colonic epithelia from patients with IBD, supporting the concept that disrupted barrier function contributes to this disorder.
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