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

Author:

Telling Glenn C.1,Parchi Piero2,DeArmond Stephen J.3,Cortelli Pietro4,Montagna Pasquale4,Gabizon Ruth5,Mastrianni James1,Lugaresi Elio4,Gambetti Pierluigi2,Prusiner Stanley B.6

Affiliation:

1. G. C. Telling and J. Mastrianni, Department of Neurology, University of California, San Francisco, CA 94143, USA.

2. P. Parchi and P. Gambetti, Division of Neuropathology, Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.

3. S. J. DeArmond, Departments of Neurology and Pathology, University of California, San Francisco, CA 94143, USA.

4. P. Cortelli, P. Montagna, E. Lugaresi, Department of Neurology, University of Bologna, Bologna 40123, Italy.

5. R. Gabizon, Department of Neurology, Hadassah Medical Center, Hebrew University, Jerusalem 91120, Israel.

6. S. B. Prusiner, Departments of Neurology and Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.

Abstract

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 .

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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