6 Doppel, a New PrP-like Mammalian Protein

Abstract

INTRODUCTION
Discovery of the Prion Protein Gene, Prnp
Prior to 1985, the genetic origin of the infectious isoform of the prion protein (Prp) was unknown: Indeed, some had speculated that PrP would prove to be encoded by the genomic nucleic acid of hypothetical spongiform encephalopathy–causing “slow virus” (Rohwer 1984). Elucidation of the amino-terminal sequence of PrP 27–30 allowed the synthesis of degenerate oligonucleotide probes and the subsequent identification of a cDNA clone that encoded all but the first 11 amino acids of the mature prion protein (Prusiner et al. 1984; Cheseboro et al. 1985; Oesch et al. 1985). A PrP cDNA clone was then used as a hybridization probe to interrogate denatured preparations of purified infectious prions, genomic DNA, and total RNA preparations isolated from the brains of healthy and prion-infected hamsters. These analyses established that, whereas DNA or RNA molecules encoding prion proteins could not be detected in denatured prion preparations, PrP gene sequences were present in the genomic DNA of hamsters (Oesch et al. 1985). This chromosomal gene, cloned and mapped the following year (Basler et al. 1986), is transcribed in both healthy and infected hamsters to generate a 2.1-kb PrP mRNA. Subsequent work identified the translation product of this mRNA in healthy animals as the protease-sensitive, α-helical glycoprotein PrP^C, setting the stage in turn for the conformational hypotheses of prion replication elaborated elsewhere in this volume.

The Rise, Fall, and Rise of the Prion Gene Complex
Although discerning the exact function of PrP^C has proven...