TRUNCATED FORMS OF THE HUMAN PRION PROTEIN IN NORMAL BRAIN AND IN PRION DISEASES

The cellular form of the prion protein (PrPc) is a glycoprotein anchor ed to the cell membrane by a glycosylphosphatidylinositol moiety. An a berrant form of PrPc that is partially resistant to proteases, PrPres, is a hallmark of prion diseases, which in humans include Creutzfeldt Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fata l familial insomnia. We have characterized the major forms of PrP in n ormal and pathological human brains. A COOH-terminal fragment of PrPc, designated C1, is abundant in normal and CJD brains as well as in hum an neuroblastoma cells. Sequence analysis revealed that C1 contains al ternative NH2 termini starting at His-111 or Met-112. Like PrPc, C1 is glycosylated, anchored to the cell membrane, and is heat stable. Cons istent with the lack of the NH2-terminal region of PrPc, C1 is more ac idic than PrPc and does not bind heparin. An additional fragment longe r than C1, designated C2, is present in substantial amounts in CJD bra ins. Like PrPres, C2 is resistant to proteases and is detergent-insolu ble. Our data indicate that C1 is a major product of normal PrPc metab olism, generated by a cleavage that disrupts the neurotoxic and amyloi dogenic region of PrP comprising residues 106-126. This region remains intact in C2, suggesting a role for C2 in prion diseases.