Claudio Soto

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Mechanisms of Transmissibility in Prion Diseases

Transmissible spongiform encephalopathies, or prion diseases, are neurodegenerative disorders that can be transmitted from animals to humans. Understanding the pathogenic process in these disorders and the mechanisms by which they are transmitted within and between species is of fundamental importance for protecting the human population as well for the development of therapeutic strategies. Project 1: Molecular and Structural Basis of Prion Protein Conversion to the Infectious Form Project Leader: Witold Surewicz DESCRIPTION (as provided by applicant): The main focus of Research Project 1 is to elucidate the structural basis of prion protein conversion and the structure of the infectious PrPSc conformer. This Project also seeks to identify specific structural differences in PrPSc that underlie phenotypic variability of human prion diseases. This contributes to the over-arching objective of the Program Project to advance the understanding of the pathogenic process in prion diseases, with a special focus on the mechanisms of disease transmission. A critical gap in TSE research is limited understanding of the structure of PrPSc. This knowledge is fundamental to understanding the mechanism of prion replication. Here we address this issue by a number of complementary approaches, ranging from studies with apparently infectious amyloid fibrils formed by fragment(s) of PrP to structural characterization of highly infectious prions generated from the recombinant full-length PrP and determination of lower-resolution strain-specific structural constraints for brain-derived PrPSc. We anticipate that at the very least, these studies will allow us to (i) identify and characterize the critical seedin element in prion protein conversion to the infectious form, both with regard to its sequence as well as high-resolution structure; (ii) conclusively establish the overall folding motif within the?-core of infectious PrPres aggregates (thereby resolving the major controversy in the field) and determine the identity of individual ?- strands and turns between them; (iii) determine which specific structural features are critical determinants of prion infectivity and use this informatio to advance the development of novel therapeutic strategy based on the concept of self-propagating 'antiprions'.