Prion protein genes and prion diseases: studies in transgenic mice

Abstract

In the past decade, manipulation of PrP genes by transgenesis in mice has provided important insights into mechanisms of prion propagation and the molecular basis of prion strains and species barriers. Despite these advances, our understanding of these unique pathogens is far from complete. This review focuses on PrP gene knockout and gene replacement studies, PrP structure and function, and transgenic models of human and animal prion diseases. Transgenic approaches will doubtless remain the cornerstone of investigations into the prion diseases in the coming years, which will include mechanistic studies of prion pathogenesis and prion transmission barriers. Transgenic models will also be important tools for the evaluation of potential therapeutic agents for prion diseases.

Slow virus disease: Deciphering conflicting data on the transmissible spongiform encephalopathies (TSE) also called prion diseases

“…The integrity of the lipid rafts is essential for initiation of scrapie infection. Prion deficient mice are not susceptible to scrapie infection (Telling, 2000). The similarity of the trafficking of prion protein through this caveolae-mediated endosomal pathway bears a striking resemblance to the Japanese model of Brucella infection wherein the prion serves as a receptor for initiating infection (Watarai et al, 2003).…”

“…The PrP host gene expression is important in determining the length of the incubation period for TSE and in limiting susceptibility to individual strains of scrapie agent (Priola et al, 2003). The removal of the PrP gene in Prnp o/o knock-out mice will inhibit scrapie infection (Telling, 2000), suggesting that PrP c is essential for infectivity (Priola et al, 2003).…”

Pathogenesis of Chronic Wasting Disease in Cervidized Transgenic Mice

“…The cosSHa.Tet cosmid expression vector contains a 49-kb DNA fragment encompassing the Syrian hamster PrP gene and has been used to produce numerous Tg models of prion diseases, including mice in which the species barriers to Syrian hamster, human, and bovine prions were eliminated. 5,6,[11][12][13][14][15][16] To increase CerPrP expression in transgenic mice, the CerPrP S2 allele plasmid nucleotide sequence was modified by site-directed mutagenesis immediately upstream of the initiating ATG to produce a consensus Kozak translation initiation sequence. Two founders were generated by microinjection of fertilized embryos from Prnp 0/0 knockout mice on an FVB/N background (FVB/Prnp 0/0 ), from which a colony of 1536 Tg[CerPrP] mice was developed.…”

Transmission of Prions from Mule Deer and Elk with Chronic Wasting Disease to Transgenic Mice Expressing Cervid PrP

“…To produce Tg(CerPrP) mice, the open reading frame (ORF) cassette of the CerPrP S2 allele (GenBank accession no.AF009180) was released from plasmid sequences following digestion with SalI and XhoI and purified ORF fragments were ligated to the SalI-cut cosSHa.Tet cosmid expression vector. The cosSHa.Tet cosmid expression vector contains a 49-kb DNA fragment encompassing the Syrian hamster PrP gene (32) and has been used to produce numerous Tg models of prion diseases (35), including mice in which the species barriers to Syrian hamster, human, and bovine prions are eliminated (1,26,30,33,37,38). To increase CerPrP expression in Tg mice, we modified the CerPrP S2 allele plasmid nucleotide sequence by site-directed mutagenesis immediately upstream of the initiating ATG to produce a consensus Kozak translation initiation sequence.…”