ABSTRACT
Introduction .................................................................................................................................. 113 Prions and the Prion Diseases ..................................................................................................... 114 Microinjection Transgenic Approaches ....................................................................................... 115
Structure-Function Studies of PrP..................................................................................... 116 Transgenic Models of Inherited Prion Diseases ................................................................ 117 Transgenic Studies of Prion Species Barriers.................................................................... 118 Transgenic Studies of Prion Strains................................................................................... 119 Transgenic Studies of Prion Pathogenesis ......................................................................... 121
Ectopic Expression Studies.......................................................................................................... 121 Knockout Mouse Models ................................................................................................... 122
Gene Targeting Approaches ......................................................................................................... 123 References .................................................................................................................................... 124
INTRODUCTION
Prion diseases have been studied for many years because of their extraordinary biology and the unique properties of the infectious agent. Because prions can only be assayed in experimental animals and the time between inoculation and disease is long, characterization of the infectious agent has been enormously difficult. On the other hand, dramatic advances in our understanding of prions and the prion diseases have occurred, in large part, precisely because they can be transmitted to experimental animals. The advent of transgenic technology has done much to further our understanding about various aspects of prion biology. Manipulation of prion protein (PrP) genes by transgenesis in mice has been accomplished using two approaches: PrP gene knockout or gene replacement using homologous recombination in embryonic stem cells and microinjection of transgenes into fertilized embryos. These studies have provided important insights into the pathogenesis of prion diseases, including the mechanism of prion propagation, the molecular basis of the species barrier, prion strains, and the mechanism by which human prion diseases can be both genetic and infectious. In this review we will focus on the role that various transgenic approaches have played in furthering our understanding of prions and prion diseases and will also outline the remaining unresolved issues in prion biology.
