Transgenic models of prion disease

There is growing concern that bovine spongiform encephalopathy (BSE) may have passed from cattle to humans, resulting in approximately 70 cases of an atypical, variant CJD (vCJD) in teenagers and young adults. We report here that transgenic (Tg) mice expressing full-length bovine (Bo) PrP serially propagate BSE prions and that there is no species barrier for transmission from cattle to Tg(BoPrP) mice. Surprisingly, these same mice were also highly susceptible to vCJD and natural sheep scrapie. The incubation times (approximately 250 d), neuropathology, and PrP(Sc) isoforms in Tg(BoPrP) mice inoculated with vCJD and BSE brain extracts were indistinguishable and differed dramatically from those seen in these mice injected with natural scrapie. In efforts to identify PrP sequences required for prion formation, we found that a redacted prion protein of only 106 amino acids (PrP106) containing two large deletions supported prion propagation. In Tg(PrP106) mice, an artificial transmission barrier for the passage of full-length mouse prions was diminished by the coexpression of full-length wt MoPrP(C), suggesting that wt MoPrP acts in trans to accelerate the replication of "miniprions" containing PrP(Sc)106. Following a single passage (approximately 300 d) in Tg(PrP106) mice, the miniprions efficiently transmitted disease to Tg(PrP106) mice after only approximately 66 days. Our findings with Tg(BoPrP) mice provide compelling evidence that prions from cattle with BSE have infected humans and caused fatal neurodegeneration, the unique features of miniprions offer new insights into the mechanism of prion replication, and the trans-acting effects of full-length PrP coexpression suggest a new approach to the development of even more efficient animal models for prion diseases.