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1 Institute for Neurodegenerative Diseases, University of California, San Francisco, California 94143, USA
2 Department of Neurology, University of California, San Francisco, California 94143, USA
3 Departments of Immunology and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA
4 Department of Medicine, University of California, San Francisco, California 94143, USA
5 Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA
6 Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, USA
Reprint requests to: Stanley B. Prusiner, Institute for Neurodegenerative Diseases, Box 0518, University of California, San Francisco, CA 94143-0518; e-mail: hang{at}itsa.ucsf.edu; fax: (415) 476-8386.
Studies of prion biology and diseases have elucidated several new concepts, but none was more heretical than the proposal that the biological properties that distinguish different prion strains are enciphered in the disease-causing prion protein (PrPSc). To explore this postulate, we examined the properties of PrPSc from eight prion isolates that propagate in Syrian hamster (SHa). Using resistance to protease digestion as a marker for the undenatured protein, we examined the conformational stabilities of these PrPSc molecules. All eight isolates showed sigmoidal patterns of transition from native to denatured PrPSc as a function of increasing guanidine hydrochloride (GdnHCl) concentration. Half-maximal denaturation occurred at a mean value of 1.48 M GdnHCl for the Sc237, HY, SHa(Me7), and MT-C5 isolates, all of which have 
75-d incubation periods; a concentration of 1.08 M was found for the DY strain with a 170-d incubation period and 1.25 M for the SHa(RML) and 139H isolates with 180-d incubation periods. A mean value of 1.39 M GdnHCl for the Me7-H strain with a 320-d incubation period was found. Based on these results, the eight prion strains segregated into four distinct groups. Our results support the unorthodox proposal that distinct PrPSc conformers encipher the biological properties of prion strains.
Keywords: Prion strains; spongiform encephalopathies; protein conformation; scrapie; prion protein; neurodegenerative disease
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