Antiprion properties of prion protein-derived cell-penetrating peptides.
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.
Löfgren
Kajsa
K
Department of Biochemistry and Biophysics, The Arrhenius Laboratories, Stockholm University, SE-106 91 Stockholm, Sweden. lofgren@dbb.su.se
Wahlström
Anna
A
Lundberg
Pontus
P
Langel
Ulo
U
Gräslund
Astrid
A
Bedecs
Katarina
K
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
D010446:Peptide Fragments; D018620:PrPSc Proteins; D011328:Prions