Mechanistic insights into prion pathogenesis and strain evolution using gene-targeted mice

Abstract

Prion diseases are a group of fatal neurological disorders that affect animals and humans with no current treatments. While it is well established that the unique mechanisms of prion replication and strain diversity derive from template-mediated conformational conversion of the normal cellular prion protein, referred to as PrPC, by its infectious counterpart, PrPSc, how prion strains evolve is less understood. Significant advancements in biological, genetic, and prion research have led to the capability of studying this pathogenetic process using recombinant proteins, in vitro models, and mammalian hosts, the latter being the gold standard for assaying prion infectivity, transmission, and strain evolution. While the development of transgenic mice that express animal or human PrP successfully abrogated the species barrier for the study of natural prions, these mice were subject to certain limitations. As a result, novel gene-targeted mice were developed that integrate exogenous mammalian PrP sequences at the murine prion protein locus. In light of the controlled expression of elk, deer, or ovine PrP in our gene-targeted mice and their attendant susceptibility to infection by peripheral as well as intracerebral routes of transmission, the objective of this dissertation was to assess the role of several factors on prion pathogenesis and strain evolution.