title: Comparison of the anti-prion mechanism of four different anti-prion compounds, anti-PrP monoclonal antibody 44B1, pentosan polysulfate, chlorpromazine, and U18666A, in prion-infected mouse neuroblastoma cells.
abstract: Molecules that inhibit the formation of an abnormal isoform of prion protein (PrP(Sc)) in prion-infected cells are candidate therapeutic agents for prion diseases. Understanding how these molecules inhibit PrP(Sc) formation provides logical basis for proper evaluation of their therapeutic potential. In this study, we extensively analyzed the effects of the anti-PrP monoclonal antibody (mAb) 44B1, pentosan polysulfate (PPS), chlorpromazine (CPZ) and U18666A on the intracellular dynamics of a cellular isoform of prion protein (PrP(C)) and PrP(Sc) in prion-infected mouse neuroblastoma cells to re-evaluate the effects of those agents. MAb 44B1 and PPS rapidly reduced PrP(Sc) levels without altering intracellular distribution of PrP(Sc). PPS did not change the distribution and levels of PrP(C), whereas mAb 44B1 appeared to inhibit the trafficking of cell surface PrP(C) to organelles in the endocytic-recycling pathway that are thought to be one of the sites for PrP(Sc) formation. In contrast, CPZ and U18666A initiated the redistribution of PrP(Sc) from organelles in the endocytic-recycling pathway to late endosomes/lysosomes without apparent changes in the distribution of PrP(C). The inhibition of lysosomal function by monensin or bafilomycin A1 after the occurrence of PrP(Sc) redistribution by CPZ or U18666A partly antagonized PrP(Sc) degradation, suggesting that the transfer of PrP(Sc) to late endosomes/lysosomes, possibly via alteration of the membrane trafficking machinery of cells, leads to PrP(Sc) degradation. This study revealed that precise analysis of the intracellular dynamics of PrP(C) and PrP(Sc) provides important information for understanding the mechanism of anti-prion agents.
authors.affiliation: Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Hasebe
authors.affiliation: Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D045744:Cell Line, Tumor; D002746:Chlorpromazine / Q000494:pharmacology; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology; D018621:PrPC Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy; D011328:Prions / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D000736:Androstenes; D058846:Antibodies, Monoclonal, Murine-Derived; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D010426:Pentosan Sulfuric Polyester; D002746:Chlorpromazine