title: Antiprion properties of prion protein-derived cell-penetrating peptides.
abstract: In prion diseases, the cellular prion protein (PrP(C)) becomes misfolded into the pathogenic scrapie isoform (PrP(Sc)) responsible for prion infectivity. We show here that peptides derived from the prion protein N terminus have potent antiprion effects. These peptides are composed of a hydrophobic sequence followed by a basic segment. They are known to have cell-penetrating ability like regular cell-penetrating peptides (CPPs), short peptides that can penetrate cellular membranes. Healthy (GT1-1) and scrapie-infected (ScGT1-1) mouse neuronal hypothalamic cells were treated with various CPPs, including the prion protein-derived CPPs. Lysates were analyzed for altered protein levels of PrP(C) or PrP(Sc). Treatment with the prion protein-derived CPPs mouse mPrP(1-28) or bovine bPrP(1-30) significantly reduced PrP(Sc) levels in prion-infected cells but had no effect on PrP(C) levels in noninfected cells. Further, presence of prion protein-derived CPPs significantly prolonged the time before infection was manifested when infecting GT1-1 cells with scrapie. Treatment with other CPPs (penetratin, transportan-10, or poly-L-arginine) or prion protein-derived peptides lacking CPP function (mPrP(23-28,) mPrP(19-30,) or mPrP(23-50)) had no effect on PrP(Sc) levels. The results suggest a mechanism by which the signal sequence guides the prion protein-derived CPP into a cellular compartment, where the basic segment binds specifically to PrP(Sc) and disables formation of prions.
authors.affiliation: Department of Biochemistry and Biophysics, The Arrhenius Laboratories, Stockholm University, SE-106 91 Stockholm, Sweden. lofgren@dbb.su.se
authors.forename: Kajsa
authors.initials: K
authors.lastname: Löfgren
authors.forename: Anna
authors.initials: A
authors.lastname: Wahlström
authors.forename: Pontus
authors.initials: P
authors.lastname: Lundberg
authors.forename: Ulo
authors.initials: U
authors.lastname: Langel
authors.forename: Astrid
authors.initials: A
authors.lastname: Gräslund
authors.forename: Katarina
authors.initials: K
authors.lastname: Bedecs
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D018620:PrPSc Proteins / Q000187:drug effects / Q000378:metabolism; D017096:Prion Diseases / Q000473:pathology / Q000517:prevention & control*; D011328:Prions / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D010446:Peptide Fragments; D018620:PrPSc Proteins; D011328:Prions