Prions - Prusiner Nobel lecture

Prions - Prusiner Nobel lecture - P roc. Natl. Acad. Sci....

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Proc. Natl. Acad. Sci. USA Vol. 95, pp. 13363–13383, November 1998 Nobel Lecture Prions S TANLEY B. P RUSINER ² Departments of Neurology and of Biochemistry and Biophysics, University of California, San Francisco, CA 94143 ABSTRACT Prions are unprecedented infectious patho- gens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt–Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible parti- cles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrP Sc ). The normal, cellular PrP (PrP C ) is converted into PrP Sc through a posttransla- tional process during which it acquires a high b -sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrP Sc . Transgenetic studies argue that PrP Sc acts as a template upon which PrP C is refolded into a nascent PrP Sc molecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should fa- cilitate structural studies of PrP Sc . While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases. The torturous path of the scientific investigation that led to an understanding of familial Creutzfeldt–Jakob disease (CJD) chronicles a remarkable scientific odyssey. By 1930, the high incidence of familial (f) CJD in some families was known (1, 2). Almost 60 years were to pass before the significance of this finding could be appreciated (3–5). CJD remained a curious, rare neurodegenerative disease of unknown etiology through- out this period of three score years (6). Only with transmission of disease to apes after inoculation of brain extracts prepared from patients who died of CJD did the story begin to unravel (7). Once CJD was shown to be an infectious disease, relatively little attention was paid to the familial form of the disease since most cases were not found in families. It is interesting to speculate how the course of scientific investigation might have proceeded had transmission studies not been performed until after the molecular genetic lesion had been identified. Had that sequence of events transpired, then the prion concept, which readily explains how a single disease can have a genetic or infectious etiology, might have been greeted with much less skepticism (8).
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Prions - Prusiner Nobel lecture - P roc. Natl. Acad. Sci....

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