Transgenic and Knockout Mice in Research on Prion Diseases

Abstract

Since the discovery of the prion protein (PrP) gene more than a decade ago, transgenetic investigations on the PrP gene have shaped the field of prion biology in an unprecedented way. Many questions regarding the role of PrP in susceptibility of an organism exposed to prions have been elucidated. For example mice with a targeted disruption of the PrP gene have allowed the demonstration that an organism that lacks PrPc is resistant to infection by prions. Reconstitution of these mice with mutant PrP genes allowed investigations on the structure-activity relationship of the PrP gene with regard to scrapie susceptibility. Unexpectedly, transgenic mice expressing PrP with specific amino-proximal truncations spontaneously develop a neurologic syndrome presenting with ataxia and cerebellar lesions. A distinct spontaneous neurologic phenotype was observed in mice with internal deletions in PrP. Using ectopic expression of PrP in PrP knockout mice has turned out to be a valuable approach towards the identification of host cells that are capable of replicating prions. Transgenic mice have also contributed to our understanding of the molecular basis of the species barrier for prions. Finally, the availability of PrP knockout mice and transgenic mice overexpressing PrP allows selective reconstitution experiments aimed at expressing PrP in neurografts or in specific populations of hemato- and lymphopoietic cells. Such studies have shed new light onto the mechanisms of prion spread and disease pathogenesis.

Prion proteins and the gut: une liaison dangereuse?

“…Furthermore, PrP Sc like proteins produced in vitro have not yet been shown to be infectious 6. The strongest evidence for the prion hypothesis comes from experiments with transgenic mice7showing that mice lacking the PrP gene are not able to propagate infectivity and develop the disease. Use of these mice in neural graft experiments has proved that PrP c is necessary for the spread of the TSE infectious agent along neuronal pathways 8.…”

NADPH oxidase and extracellular regulated kinases 1/2 are targets of prion protein signaling in neuronal and nonneuronal cells

“…It is majorly expressed in neuronal cells where TSE-associated damages occur. Knockout experiments (1) have not unraveled any physiological role of PrP C . However, ex vivo studies using cells from PrP null mice or prion-infected cells revealed alterations in copper metabolism and enhanced susceptibility to oxidative stress (2,3).…”

Markedly Increased Susceptibility to Natural Sheep Scrapie of Transgenic Mice Expressing Ovine PrP

“…There is compelling genetic evidence that transmission of TSEs is tightly controlled by the PrP-encoding gene (Prnp) (38,40,52). Apart from modulating the individual susceptibility to the disease through natural polymorphism or mutation, PrP appears to play a critical role in determining the prion host range.…”