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Mechanisms of prion antagonization by PrP-derived cell-penetrating peptides
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.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Cell penetrating peptides derived from the prion protein N-terminus (PrP-CPPs) reduce PrPSc levels in prion-infected neuronal cell cultures (1). The PrP-CPPs consist of the hydrophobic PrP signal sequence followed by a basic segment (KKRPKP) and enter cells through raft-dependent macropinocytosis. To decipher the PrP-CPP anti-prion mechanism, different peptide constructs were analyzed for effects on PrPSc levels in GT1-1 neuronal cell cultures infected with either prion strain RML or 22L. For both strains, the PrP-CPPs antagonized the infection, but RML and 22L-infections differed in sensitivity to the PrP-CPP anti-prion effect. We also show that the effect on PrPSc levels does not depend on peptide interaction with any chiral receptor. The signal sequence segment of the PrP-CPPs promotes a specific positioning within the cell where conversion may occur, as signal sequence segment shortening or targeting of the KKRPKP-motif into alternative sub-cellular compartments disrupts the peptide anti-prion effect. Defining the anti-prion mechanism of PrP-CPPs is a matter of establishing how the peptides connect to the prion replicative interface. As the conversion process is poorly understood, the PrP-CPPs represent useful tools to outline the sub-cellular context of prion propagation.

Keyword [en]
Creutzfeldt–Jakob disease, nuclear localization signal, lipid rafts, protein transduction domain
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-44379OAI: oai:DiVA.org:su-44379DiVA: diva2:369433
Available from: 2010-11-11 Created: 2010-11-08 Last updated: 2016-01-29Bibliographically 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)
Opponent
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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