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7 Knockouts, Transgenics, and Transplants in Prion Research

C. Weissmann, A.J. Raeber, D. Shmerling, A. Aguzzi, J.C. Manson


Compelling linkage between the infectious scrapie agent, or prion, and PrP was established by biochemical and genetic data (Prusiner 1982Prusiner 1989; Gabizon et al. 1988; Hsiao et al. 1989; Scott et al. 1989; Weissmann 1989), leading to the prediction that animals devoid of PrP should be resistant to experimental scrapie and fail to propagate infectivity. This prediction was indeed borne out, adding support to the protein-only hypothesis. In addition, the availability of PrP knockout mice provided an approach to new lines of investigation.

Generation of PrP Knockout Mice
Three lines of mice devoid of PrPC have been generated by homologous recombination, using different strategies. Büeler et al. (1992) replaced PrP codons 4–187 (of a total of 254 codons), about 80% of the sequence encoding the mature protein (residues 22–230), by a neo cassette. Mice homozygous for the disrupted gene on a mixed C57BL-129/Sv genetic background (designated in this chapter as Prnp0/0[Zürich]) expressed truncated PrP mRNA but no detectable PrP fragment and developed normally. Manson et al. (1994b) prepared a line of PrP knockout mice (Prnp−/−[Edinburgh]) in which the PrP gene was disrupted by the insertion of a neo cassette into a unique KpnI site (following codon 93) of the PrP open reading frame. Mice homozygous for the knockout allele, on a pure 129/Ola background, also developed normally, and no PrP mRNA or PrP-related protein was detected in the brain.

A third line of PrP knockout mice, Prnp−/−[Nagasaki], in which 200...

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