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Antiprion properties of prion protein-derived cell-penetrating peptides
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0001-6107-0844
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2008 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 22, no 7, 2177-2184 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2008. Vol. 22, no 7, 2177-2184 p.
Keyword [en]
scrapie, prion conversion, N terminus, therapy, signal peptide
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-14492DOI: 10.1096/fj.07-099549ISI: 000257292500010OAI: oai:DiVA.org:su-14492DiVA: diva2:181012
Available from: 2009-01-12 Created: 2009-01-12 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Interactions of Prion Proteins and PrP-derived Peptides in Scrapie infection
Open this publication in new window or tab >>Interactions of Prion Proteins and PrP-derived Peptides in Scrapie infection
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prion diseases are fatal and incurable spongiform encephalopathies that occur amongst mammals. The central pathological event is the misfolding of the cellular prion protein (PrPC) into an amyloid, neurotoxic isoform called scrapie (PrPSc). PrPSc is the main, or sole, constituent of infectious prions. PrPSc resists cellular degradation and also induces misfolding of PrPC via a process called conversion. Conversion seems to be an endocytotic event implicating auxiliary cellular cofactors interacting with PrPC and/or PrPSc. The aim of this thesis is to decipher and modulate key events involved in prion conversion and cytopathology, by studying persistently scrapie infected murine neuronal cell cultures. This work shows that cell penetrating peptides derived from the prion protein (PrP-CPPs) can suppress cellular PrPSc levels. The PrP-CPPs assert these actions on two prion strains regardless of peptide configuration and do not inhibit any PrP-interaction with heparan sulfate (HS) proteoglycans (PG). A polybasic motif in the PrP-CPPs may interact with PrPSc, but the anti-prion effect is controlled by a signal peptide sequence. The PrP-CPPs represents a novel form of prion antagonizing compound. Prion-induced alterations in protein expression, cellular localization, activity and metabolism, designate putative mediators of disease or neuroprotective defence mechanisms. We report on interplay between the HSPG glypican-1 (Gpc-1) and scrapie-infection. Gpc-1 is aberrantly distributed in scrapie-infected cells and HS degradation by autocatalytic deaminative cleavage is elevated, suggestively in order to restrain PrPSc levels. Additionally, we demonstrate that scrapie-infection elevates the activity of Src family kinase members Src and Fyn, in part by affecting Src expression and Fyn membrane distribution. This causes an uncontrolled tyrosine phosphorylation which could contribute to neuronal loss in vivo.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2010. 132 p.
Keyword
Spongiform encephalopathy, Creutzfeldt-Jakob disease, Amyloidosis, Neurodegeneration, Cell penetrating peptide, Protein Transduction Domain, Heparan sulfate, Proteoglycan, Glypican, Src family kinase, Fyn
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-45736 (URN)978-91-7447-179-3 (ISBN)
Public defence
2010-12-21, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
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Supervisors
Note
At the time of the doctoral defence the following paper was unpublished and had a status as follows: Paper nr. 5: ManuscriptAvailable from: 2010-11-29 Created: 2010-11-10 Last updated: 2010-12-03Bibliographically approved

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Löfgren, KajsaWahlström, AnnaLangel, ÜloGräslund, Astrid
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