Abstract
Conversion of the cellular alpha-helical prion protein (PrP(C)) into a disease-associated isoform (PrP(Sc)) is central to the pathogenesis of prion diseases. Molecules targeting either normal or disease-associated isoforms may be of therapeutic interest, and the antibodies binding PrP(C) have been shown to inhibit prion accumulation in vitro. Here we investigate whether antibodies that additionally target disease-associated isoforms such as PrP(Sc) inhibit prion replication in ovine PrP-inducible scrapie-infected Rov cells. We conclude from these experiments that antibodies exclusively binding PrP(C) were relatively inefficient inhibitors of ScRov cell PrP(Sc) accumulation compared with antibodies that additionally targeted disease-associated PrP isoforms. Although the mechanism by which these monoclonal antibodies inhibit prion replication is unclear, some of the data suggest that antibodies might actively increase PrP(Sc) turnover. Thus antibodies that bind to both normal and disease-associated isoforms represent very promising anti-prion agents.
Highlights
Conversion of the cellular ␣-helical prion protein (PrPC) into a disease-associated isoform (PrPSc) is central to the pathogenesis of prion diseases
Monoclonal Antibodies Raised against -PrP Inhibit More Efficiently PrPSc Accumulation in scrapieinfected epithelial Rov (ScRov) Cells—In initial studies, we assessed how efficiently ICSM 4, 17, 18, and 19 raised against ␣-PrP and ICSM 35 raised against -PrP inhibited prion replication (Table I)
Triplicate cultures of ScRov cells were treated with monoclonal antibodies (mAbs) concentrations ranging from 10 ng/ml to 10 g/ml
Summary
PrPSc, disease-associated isoform of prion protein; PrPC, cellular prion protein; mAb, monoclonal antibody; DS500, dextran sulfate 500; PBS, phosphate-buffered saline. Recent reports indicate that anti-PrP monoclonal antibodies (mAbs) efficiently inhibit PrPSc accumulation in ScN2a mouse neuroblastoma cells [7, 8] and in infected transgenic mice engineered to produce one of these mAbs, 6H4 [9]. Their efficiency was related directly to their epitope and to their affinity for PrPC [10, 11]. We found that the inhibition by several mAbs was similar and even greater than turning off the production of the PrPC substrate, suggesting antibody-mediated enhancement of the proteolysis of intracellular PrPSc
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