TRANSGENIC AND KNOCKOUT MICE IN RESEARCH ON PRION DISEASES

Since the discovery of the prion protein (PrP) gene more than a decade ago, transgenetic investigations on the PrP gene have shaped the fiel d of prion biology in an unprecedented way, Many questions regarding t he role of PrP in susceptibility of an organism exposed to prions have been elucidated, For example mice with a targeted disruption of the P rP gene have allowed the demonstration that an organism that lacks PrP c is resistant to infection by prions, Reconstitution of these mice wi th mutant PrP genes allowed investigations on the structure-activity r elationship of the PrP gene with regard to scrapie susceptibility, Une xpectedly, transgenic mice expressing PrP with specific amino-proximal truncations spontaneously develop a neurologic syndrome presenting wi th ataxia and cerebellar lesions, A distinct spontaneous neurologic ph enotype was observed in mice with internal deletions in PrP, Using ect opic expression of PrP in PrP knockout mice has turned out to be a val uable approach towards the identification of host cells that are capab le of replicating prions, Transgenic mice have also contributed to our understanding of the molecular basis of the species barrier for prion s. Finally, the availability of PrP knockout mice and transgenic mice overexpressing PrP allows selective reconstitution experiments aimed a t expressing PrP in neurografts or in specific populations of hemato- and lymphopoietic cells, Such studies have shed new light onto the mec hanisms of prion spread and disease pathogenesis.