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(American Journal of Pathology. 1998;153:1561-1572.)
© 1998 American Society for Investigative Pathology

Regular Articles

Endogenous Proteolytic Cleavage of Normal and Disease-Associated Isoforms of the Human Prion Protein in Neural and Non-Neural Tissues

Adolfo Jiménez-Huete* , Patricia M. J. Lievens , Rubén Vidal* , Pedro Piccardo , Bernardino Ghetti , Fabrizio Tagliavini , Blas Frangione* and Frances Prelli*

From the Department of Pathology,* New York University Medical Center, New York, New York; the Istituto Nazionale Neurologico Carlo Besta, Milano, Italy and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana

We have investigated the proteolytic cleavage of the cellular (PrP^C) and pathological (PrP^Sc) isoforms of the human prion protein (PrP) in normal and prion-affected brains and in tonsils and platelets from neurologically intact individuals. The various PrP species were resolved after deglycosylation according to their electrophoretic mobility, immunoreactivity, Sarkosyl solubility, and, as a novel approach, resistance to endogenous proteases. First, our data show that PrP^C proteolysis in brain originates amino-truncated peptides of 21 to 22 and 18 (C1) kd that are similar in different regions and are not modified by the PrP codon 129 genotype, a polymorphism that affects the expression of prion disorders. Second, this proteolytic cleavage of PrP^C in brain is blocked by inhibitors of metalloproteases. Third, differences in PrP^C proteolysis, and probably in Asn glycosylation and glycosylphosphatidylinositol anchor composition, exist between neural and non-neural tissues. Fourth, protease-resistant PrP^Sc cores in sporadic Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker F198S disease brains all have an intact C1 cleavage site (Met111-His112), which precludes disruption of a domain associated with toxicity and fibrillogenesis. Fifth, the profile of endogenous proteolytic PrP^Sc peptides is characteristic of each disorder studied, thus permitting the molecular classification of these prion diseases without the use of proteinase K and even a recognition of PrP^Sc heterogeneity within type 2 CJD patients having different codon 129 genotype and neuropathological phenotype. This does not exclude the role of additional factors in phenotypic expression; in particular, differences in glycosylation that may be especially relevant in the new variant CJD. Proteolytic processing of PrP may play an important role in the neurotropism and phenotypic expression of prion diseases, but it does not appear to participate in disease susceptibility.

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