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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.07-099549v1 22/7/2177    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Löfgren, K. Articles by Bedecs, K. PubMed PubMed Citation Articles by Löfgren, K. Articles by Bedecs, K.

Antiprion properties of prion protein-derived cell-penetrating peptides

Kajsa Löfgren^*,1, Anna Wahlström^*, Pontus Lundberg, Ülo Langel, Astrid Gräslund^*,1 and Katarina Bedecs^*

^* Department of Biochemistry and Biophysics, The Arrhenius Laboratories; and

Department of Neurochemistry and Neurotoxicology, Stockholm University, Stockholm, Sweden

¹Correspondence: Department of Biochemistry and Biophysics, The Arrhenius Laboratories, Stockholm University, SE-106 91 Stockholm, Sweden. E-mail: K.L., lofgren{at}dbb.su.se; A.G., astrid{at}dbb.su.se

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, K., Wahlström, A., Lundberg, P., Langel, U., Gräslund, A., and Bedecs, K. Antiprion properties of prion protein-derived cell-penetrating peptides.

Key Words: scrapie • prion conversion • N terminus • therapy • signal peptide