Biology and Pathology of Prion Diseases:
Genetic Linkage of TSE Traits to the Prion Protein Gene
The demonstrated transmissibility of TSEs suggested a contagious spread of the disease; however, some forms of TSEs like GSS and a subset of CJD appeared to be associated with families, resembling a genetic disease. In 1989, Hsiao and coworkers reported the identification of a mutation in the PrP gene which was linked to the occurrence of GSS in an autosomal dominant pattern (Hsiao et al., 1989). Since then, several more mutations in the PrP gene were shown to be linked to the occurrence of GSS or familial CJD (reviewed by Kitamoto and Tatieishi, 1994). When the GSS-associated mutation described by Hsiao and co-workers in 1989 was introduced into transgenic mice, these mice subsequently developed a neurodegenerative disease with detectable, albeit low production of infectivity (Hsiao et al., 1990; Hsiao et al., 1994). Taken together, the above results suggest that certain mutations in the PrP gene are able to trigger a spongiform encephalopathy.
Subsequently, mice homozygous for an ablated PrP gene were shown to be resistant to scrapie (Büeler et al., 1993) establishing that an intact PrP gene is a prerequisite for infection and/or prion propagation.
Genetic linkage to the PrP gene was also observed for the so-called species barrier for infection. Normally, experimental transmission between different species requires high doses of infectivity and results in long incubation times (Pattison, 1965, 1966). Once transmission to a new species has been established, however, subsequent passaging within this species can be done with lower doses and results in shorter incubation times. The infectious agent is therefore specific for the host species it is produced in. When transgenic mice expressing hamster PrP in addition to their own mouse PrP were inoculated with infectious material from hamster, they exhibited much shorter incubation times than wild type mice and produced hamster-specific infectivity (Scott et al., 1989; Prusiner et al., 1990). Subsequent studies established that the species specificity resided within the coding sequence of the PrP gene (Scott et al., 1993).
Differences in scrapie incubation times between different mouse strains have been shown to be linked to the Sinc/Prn-i gene, whose genetic localization has been mapped closely to the Prn-p gene (Dickinson and Meikle, 1971; Carlson et al., 1986, 1993; Bruce and Dickinson, 1987; Hunter et al., 1987). It has not been formally proven, however, that Sinc/Prn-i is identical to Prn-p.
The genetic traits mapped to the PrP gene locus may also be linked to other, unknown genes at the same locus. Goldgaber (1991) and Hewinson and co-workers (1991) provided findings implicating the existence of an ´anti-PrP´ gene on the DNA strand opposite to the PrP coding sequence. This ´anti-PrP´ was suggested to be responsible for properties formerly ascribed to PrP. A subsequent study, presented in this thesis, provided evidence against the conjectured ´anti-PrP´ expression (Moser et al., 1993) refuting the hypothesis that genetic traits mapped to the Prn-p locus may represent inherent properties of an ´anti-PrP´ gene.