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Published as doi: 10.1096/fj.07-099549.
 (The FASEB Journal. 2008;22:2177-2184.)
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Antiprion properties of prion protein-derived cell-penetrating peptides

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

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

{dagger} 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 (PrPC) becomes misfolded into the pathogenic scrapie isoform (PrPSc) 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 PrPC or PrPSc. Treatment with the prion protein-derived CPPs mouse mPrP1–28 or bovine bPrP1–30 significantly reduced PrPSc levels in prion-infected cells but had no effect on PrPC 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 (mPrP23–28, mPrP19–30, or mPrP23–50) had no effect on PrPSc 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 PrPSc 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






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