Interactions of Prion Proteins and PrP-derived Peptides in Scrapie infection
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
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
Biochemistry and Molecular Biology
Research subject Biochemistry
IdentifiersURN: urn:nbn:se:su:diva-45736ISBN: 978-91-7447-179-3OAI: oai:DiVA.org:su-45736DiVA: diva2:369696
2010-12-21, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Fändrich, Marcus, Professor
Gräslund, Astrid, Professor
At the time of the doctoral defence the following paper was unpublished and had a status as follows: Paper nr. 5: Manuscript2010-11-292010-11-102010-12-03Bibliographically approved
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