Prion protein expression and functional importance in developmental angiogenesis: role in oxidative stress and copper homeostasis.

Nadia Alfaidy (1, 2) , Sylvain Chauvet (3) , Sandrine Andrei (3) , Aude Salomon (1, 2) , Yasmina Saoudi (4) , Pierre Richaud (5) , Catherine Aude-Garcia (3) , Pascale Hoffmann (1, 2, 6) , Annie Andrieux (7) , Jean-Marc Moulis (3) , Jean-Jacques Feige (1, 2) , Mohamed Benharouga (3)

1 BCI - Biologie du Cancer et de l'Infection
2 UJF - Université Joseph Fourier - Grenoble 1
3 LCBM - UMR 5249 - Laboratoire de Chimie et Biologie des Métaux
4 INSERM U836, équipe 1, Physiopathologie du cytosquelette
5 BVME - Biologie végétale et microbiologie environnementale - UMR7265
6 Département de Gynécologie, Obstétrique et Médecine de la Reproduction
7 INSERM U836, équipe 1, Physiopathologie du cytosquelette

AIM: It has been convincingly shown that oxidative stress and toxicity by deregulated metals, such as copper (Cu), are tightly linked to the development of pre-eclampsia and intrauterine growth retardation (IUGR), the most threatening pathologies of human pregnancy. However, mechanisms implemented to control these effects are far from being understood. Among proteins that bind Cu and insure cellular protection against oxidative stress is the cellular prion protein (PrP(C)), a glycosyl phosphatidyl inositol-anchored glycoprotein, which we reported to be highly expressed in human placenta. Herein, we investigated the pathophysiological role of PrP(C) in Cu and oxidative stress homeostasis in vitro using human placenta and trophoblast cells, and in vivo using three strains of mice (C57Bl6, PrP(C) knockout mice [PrP(-/-)], and PrP(C) overexpressing mice [Tga20]). RESULTS: At the cellular level, PrP(C) protection against oxidative stress was established in multiple angiogenic processes: proliferation, migration, and tube-like organization. For the animal models, lack (PrP(-/-)) or overexpression (Tga20) of PrP(C) in gravid mice caused severe IUGR that was correlated with a decrease in litter size, changes in Cu homeostasis, increase in oxidative stress response, development of hypoxic environment, failure in placental function, and maintenance of growth defects of the offspring even 7.5 months after delivery. INNOVATION: PrP(C) could serve as a marker for the idiopathic IUGR disease. CONCLUSION: These findings demonstrate the stress-protective role of PrP(C) during development, and propose PrP(C) dysregulation as a novel causative element of IUGR.

Domaines: Biologie cellulaire

Nadia Alfaidy, Sylvain Chauvet, Sandrine Andrei, Aude Salomon, Yasmina Saoudi, et al.. Prion protein expression and functional importance in developmental angiogenesis: role in oxidative stress and copper homeostasis.. Antioxidants and Redox Signaling, 2013, 18 (4), pp.400-11. ⟨10.1089/ars.2012.4637⟩. ⟨inserm-00734867⟩