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Altered membrane distribution and increased Fyn activity in scrapie-infected neuronal cells
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 Biochemistry and Biophysics.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The suggested cause of Prion diseases is conversion of the cellular prion protein (PrPC) into aberrant scrapie prion protein (PrPSc) isoform triggered by the latter. PrPC is localized to membrane rafts, subdomains which are implicated in conversion. In this report we have analyzed the expression, plasma membrane distribution and activity of the raft associative Src family kinase member Fyn, in scrapie-infected neuronal cell lines. As a result of prion infection, the specific tyrosine kinase activity of Fyn is increased, although the protein level of Fyn kinase is reduced. This results in an increased overall tyrosine phosphorylation in the infected cells. Interestingly, prion infection also induced a membrane redistribution of Fyn from non-raft to raft-membrane subdomains, following the distribution of PrPSc, as shown by immunoblotting of flotation-fractions after density gradient centrifugation of Triton X-100 extracted cell extracts. This indicates a persistent Fyn activation, possibly due to clustering of intracellular Fyn kinases as a result of PrPSc association to membrane rafts. An increased Fyn kinase activity followed by a dramatic increase in tyrosine phosphorylation may cause and/or contribute to synaptic disorganization and loss which are fundamental features of prion disease.

Keyword [en]
Creutzfelt-Jacobs disease, detergent resistant membranes, lipid rafts, GT1, RML
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Neurochemistry and Neurotoxicology
Identifiers
URN: urn:nbn:se:su:diva-44380OAI: oai:DiVA.org:su-44380DiVA: diva2:369435
Available from: 2010-11-11 Created: 2010-11-08 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.
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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