Evidence for the Conformation of the Pathologic Isoform of the Prion Protein Enciphering and Propagating Prion Diversity

• Published in: Science (American Association for the Advancement of Science) 1996-12, Vol.274 (5295), p.2079-2082
• Main Authors: Telling, Glenn C., Parchi, Piero, DeArmond, Stephen J., Cortelli, Pietro, Montagna, Pasquale, Gabizon, Ruth, Mastrianni, James, Lugaresi, Elio, Gambetti, Pierluigi, Prusiner, Stanley B.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain; Brain - pathology; Brain Chemistry; Cellular biology; Creutzfeldt Jakob syndrome; Creutzfeldt-Jakob disease; Creutzfeldt-Jakob Syndrome - metabolism; Creutzfeldt-Jakob Syndrome - pathology; Degeneration; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease; Disease transmission; Genetic mutation; Humans; Inoculation; Medical sciences; Mice; Mice, Transgenic; Molecules; Nerve degeneration; Nervous system; Nervous system diseases; Neurology; Patients; Prion diseases; Prion Diseases - etiology; Prion Diseases - metabolism; Prion Diseases - pathology; Prion Diseases - transmission; Prions; Prions (Proteins); Prions - chemistry; Protein Conformation; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins; PrPSc Proteins - analysis; PrPSc Proteins - chemistry; Thalamus
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.274.5295.2079

The fundamental event in prion diseases seems to be a conformational change in cellular prion protein (PrP$^C$) whereby it is converted into the pathologic isoform PrP$^{Sc}$. In fatal familial insomnia (FFI), the protease-resistant fragment of PrP$^{Sc}$ after deglycosylation has a size of 19 kilodaltons, whereas that from other inherited and sporadic prion diseases is 21 kilodaltons. Extracts from the brains of FFI patients transmitted disease to transgenic mice expressing a chimeric human-mouse PrP gene about 200 days after inoculation and induced formation of the 19-kilodalton PrP$^{Sc}$ fragment, whereas extracts from the brains of familial and sporadic Creutzfeldt-Jakob disease patients produced the 21-kilodalton PrP$^{Sc}$ fragment in these mice. The results presented indicate that the conformation of PrP$^{Sc}$ functions as a template in directing the formation of nascent PrP$^{Sc}$ and suggest a mechanism to explain strains of prions where diversity is encrypted in the conformation of PrP$^{Sc}$.