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Johanna Cormenier

The cellular prion protein (PrPC) in Cystic Fibrosis: Role in the maintenance of the epithelial bronchial barrier



English Web page.
Published on 16 December 2019
Thesis presented December 16, 2019

Abstract:
One of the pathophysiological features of cystic fibrosis (CF) disease is the loss of the tightness of the intestinal and bronchial epithelial barrier (EB). This process participates in the transmigration of inflammatory cells as well as pathogens, such as Pseudomonas aeruginosa (P.A). However, the underlying mechanisms are still poorly understood. The involvement of the CFTR protein has recently been proposed in this phenomenon, yet its apical and not lateral localization suggests the involvement of other factors in the maintenance of EB. Recently, we identified the cellular prion protein (PrPC) as a partner of adherens (AJ) and desmosome junctions (DJ) proteins in human bronchial cells. In these cells, PrPC is first addressed to the apical membrane before being redirected to the lateral membrane where it interacts, stabilizes and protects the AJ and DJ proteins against oxidative stress. Nevertheless, the role of the PrPC protein in CF, particularly in the control of the EB, remains unknown.
Thus, the objectives of my thesis were to characterize in vitro (cell lines) and in vivo (animal models), in the context of CF, i) the expression, localization and biochemical profile of the PrPC protein, ii) the expression of junctional proteins and their interactions with PrPC protein and the impact of wild type and mutated CFTR (dF508) on the trafficking and membrane stability of PrPC protein, and finally iii) the involvement of PrPC protein in neutrophils and P.A transmigration in the CF airways.
Altogether, the results showed for the first time that in CF the PrPC protein is not correctly addressed to the lateral membrane where it interacts and stabilizes the junctional proteins. The lack of PrPC trafficking from the apical to the lateral membrane appears to be linked to the CFTR mutation. As a result, the EB loses its effectiveness and becomes permissive to neutrophils and pathogens like P.A.

Keywords:
CFTR, PrPC, Cystic Fibrosis, inflammation, epithelial barrier, junctional proteins, Pseudomonas aeruginosa

On-line thesis.