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Role of polymorphic variants of the prion protein on the resistance/susceptibility to prion infection

AUTOR/es: Patricia Aguilar Calvo

DIRECTOR/es: Juan María Torres Trillo | Juan Carlos Espinosa Martín


PALABRAS CLAVE: oveja, PrP, prion, scrapie, cabra, ratones transgénicos, resistencia

A fundamental event in the pathogenesis of prion diseases is the misfolding of host cellular prion protein (PrPC) into pathological prion protein (PrPSc). Prion strains as well as certain amino acid changes in the PrPC sequence can affect the efficiency of PrPSc replication and prion transmission. The main objective of this thesis is to improve our understanding of the molecular mechanisms driving the susceptibility/resistance to prion infection. For this, we generated a panel of transgenic (Tg) mouse lines expressing either the goat wild type PrPC or this PrPC with single amino acid exchanges corresponding to goat or sheep PrPC polymorphic variants (I/M142, R/H154, R/Q211, Q/K222, Q/R171, and N/K176) that were subsequently challenged with several prion strains. Their susceptibilities were assessed and compared to determine the individual effect of each PrPC variant in the resistance/susceptibility to prion infection. In parallel, experimental goat inoculations with either a scrapie field case or a goat-BSE isolate were performed, and their results were compared with those obtained in the transmission studies in Tg mice. In this way, we were able to confirm in the natural host (goats) the reliability of our results for mouse models and to evaluate the effect of PrPC polymorphic variants on the susceptibility of goats to prion infection.

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