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Involvement of glypican-1 autoprocessing in scrapie infection.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Division of Neuroscience, Department of Experimental Medical Science, Lund University.
Division of Neuroscience, Department of Experimental Medical Science, Lund University.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2008 (English)In: Europena Journal of Neuroscience, ISSN 1460-9568, Vol. 28, no 5, 964-72 p.Article in journal (Refereed) Published
Abstract [en]

The copper-binding cellular prion protein (PrP(C)) and the heparan sulphate (HS)-containing proteoglycan glypican-1 (Gpc-1) can both be attached to lipid rafts via their glycosylphosphatidylinositol anchors, and copper ions stimulate their cointernalization from the cell surface to endosomes. The prion protein controls cointernalization and delivers copper necessary for S-nitrosylation of conserved cysteines in the Gpc-1 core protein. Later, during recycling through endosomal compartments, nitric oxide can be released from the S-nitroso groups and catalyses deaminative degradation and release of the HS substituents. Here, by using confocal immunofluorescence microscopy, we show that normal PrP(C) and Gpc-1 colocalize inside GT1-1 cells. However, in scrapie-infected cells (ScGT1-1), Gpc-1 protein remained at the cell surface separate from the cellular prion protein. Scrapie infection stimulated Gpc-1 autoprocessing and the generated HS degradation products colocalized with intracellular aggregates of the disease-related scrapie prion protein isoform (PrP(Sc)). Coimmunoprecipitation experiments demonstrated an association between Gpc-1 and PrP(C) in uninfected cells, and between HS degradation products and PrP(Sc) in infected cells. Silencing of Gpc-1 expression or prevention of Gpc-1 autoprocessing elevated the levels of intracellular PrP(Sc) aggregates in infected cells. These results suggest a role for Gpc-1 autoprocessing in the clearance of PrP(Sc) from infected cells.

Place, publisher, year, edition, pages
Wiley InterScience (Blackwell) , 2008. Vol. 28, no 5, 964-72 p.
Keyword [en]
heparan sulphate, nitric oxide, prion, proteoglycan, recycling
URN: urn:nbn:se:su:diva-14843DOI: 10.1111/j.1460-9568.2008.06386.xISI: 000258729200013PubMedID: 18717736OAI: diva2:181363
Available from: 2009-01-12 Created: 2009-01-12 Last updated: 2010-11-12Bibliographically 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.
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
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)
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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