Since its creation (1998) the general objective of the group "Molecular and Cellular Biology of Prions" has been the study of the biology and pathogenesis of prions. To do this, we have developed a collection of models based on transgenic mice that express different sequences of the Cellular Prion Protein (PrPC). These models include transgenic mice that express PrPC from different livestock species (bovine, swine, ovine or caprine), which are highly sensitive bioassays for the detection of prions from these species. These models are being very useful for the study of the molecular elements that modulate the pathology and the species barrier of the different strains of prions. At present, our purpose is to continue a series of projects aimed at identifying and characterizing the different circulating prion strains in the different livestock species. Our objective is to analyze the intra- and inter-species transmission capacity of these agents as well as their biochemical and histopathological properties, using our transgenic mouse models. These studies are providing key information to determine the diversity of circulating prion strains in livestock species and the risk that each one constitutes to the human species.
We are also undertaking studies aimed at determining the molecular elements involved in susceptibility/resistance to prion infection. To do this, we have generated a collection of transgenic mice that express different polymorphic variants of the sheep and goat PrPC to determine the individual role of each of these variants in resistance to infection with different strains of prions. This information is of great importance to design future appropriate genetic selection programs to control and eradicate prions in livestock species. On the other hand, following a similar strategy, we are studying the effect of various polymorphic variants of human PrPC on the susceptibility of human to infection with different strains of prions. Among others, we have developed two lines of transgenic mice that express the V129 or M129 variants of human PrPC to compare their respective susceptibilities to different prion isolates.
Finally, to advance in the study of the molecular elements involved in the replication and pathogenesis of prions, we have developed a collection of transgenic mice that express various potentially pathogenic mutations of PrP. The results obtained to date, together with those published by other groups, show that certain mutations in PrPC can be pathogenic, but only in some of them, it has been possible to demonstrate the transmissibility of the disease produced, suggesting a dissociation between the pathogenesis and prion infectivity. Our models of spontaneous disease, both infectious and non-infectious, constitute a valuable tool to distinguish between those processes involved in the development of the disease and those involved in the replication/transmission of prions.
The study of the replication and transmission mechanisms of prions will contribute to the design of control strategies for these diseases in livestock species and their transmission to humans. On the other hand, these results will also contribute to advancing the knowledge of other neurodegenerative diseases that occur with processes of aggregation and accumulation of other proteins such as β-amyloid, tau, α-synuclein and that seem to share some aspects of their pathogenetic mechanism; causing a variety of diseases called "prion-like diseases" in humans and/or animals such as Alzheimer's, Parkinson's, Huntington's disease, type II diabetes mellitus or amyloidosis. Many experimental results suggest that the abnormal folding of these proteins can self-propagate and transmit in a similar way to prions. In today's society, there is a growing demand for higher food safety standards reducing the risk of food for people's health to minimum levels. The transmission capacity of the different prion strains in livestock species and humans and its implications for food safety and public health highlights the great socio-economic impact worldwide of our work. On the other hand, neurodegenerative diseases are acquiring great relevance in today's society. Advancing knowledge and control of these diseases is an urgent need for an increasingly ageing society, in which the control of these neurodegenerative diseases constitutes a great challenge to overcome.
