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Subcellular distribution and physicochemical properties of scrapie-associated precursor protein and relationship with scrapie agent

Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD

We studied the biologic properties of hamster-adapted scrapie (strain 263K) and its relationship to the precursor protein of scrapie (PrP33–35^Sc). The highest titer of infectious material and the greatest concentration of PrP33-35^sc were in the fractions containing microsomal and synaptosomal membranes. We found traces of infectivity in the absence of PrP33–35^Sc associated with matrix protein. Partitioning of membranes with neutral chloroform-methanol resulted in concentration of PrP33–35^Sc and infectivity within the interphase layer. Recombination of membrane glycoproteins (interphase) with lipids extracted from homologous brains decreased infectivity 24 logs. Temperature-dependent phase separation of infected synaptosomal and microsomal membranes with Triton X-114 yielded a phospholipid-rich phase containing a high concentration of PrP33–35^S and greatest infectivity titers. This material spontaneously formed liposomes, indicating that PrP33–35^Sc and PrP33–35^C precursor proteins are highly hydrophobic intrinsic membrane components integrated with phospholipids. Homologous membrane phospholipids appear to prevent aggregation of the scrapie isoform of PrP and maintain high levels of infectivity.

Address correspondence and reprint requests to Dr. Clarence J. Gibbs, Jr., Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.

Received March 28,1989. Accepted for publication in final form August 25,1989.