Document Detail


Monoacylated cellular prion protein modifies cell membranes, inhibits cell signaling, and reduces prion formation.
MedLine Citation:
PMID:  21212283     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Prion diseases occur following the conversion of the cellular prion protein (PrP(C)) into a disease related, protease-resistant isoform (PrP(Sc)). In these studies, a cell painting technique was used to introduce PrP(C) to prion-infected neuronal cell lines (ScGT1, ScN2a, or SMB cells). The addition of PrP(C) resulted in increased PrP(Sc) formation that was preceded by an increase in the cholesterol content of cell membranes and increased activation of cytoplasmic phospholipase A(2) (cPLA(2)). In contrast, although PrP(C) lacking one of the two acyl chains from its glycosylphosphatidylinositol (GPI) anchor (PrP(C)-G-lyso-PI) bound readily to cells, it did not alter the amount of cholesterol in cell membranes, was not found within detergent-resistant membranes (lipid rafts), and did not activate cPLA(2). It remained within cells for longer than PrP(C) with a conventional GPI anchor and was not converted to PrP(Sc). Moreover, the addition of high amounts of PrP(C)-G-lyso-PI displaced cPLA(2) from PrP(Sc)-containing lipid rafts, reduced the activation of cPLA(2), and reduced PrP(Sc) formation in all three cell lines. In addition, ScGT1 cells treated with PrP(C)-G-lyso-PI did not transmit infection following intracerebral injection to mice. We propose that that the chemical composition of the GPI anchor attached to PrP(C) modified the local membrane microenvironments that control cell signaling, the fate of PrP(C), and hence PrP(Sc) formation. In addition, our observations raise the possibility that pharmacological modification of GPI anchors might constitute a novel therapeutic approach to prion diseases.
Authors:
Clive Bate; Alun Williams
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-01-06
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-03-30     Completed Date:  2011-05-16     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8752-8     Citation Subset:  IM    
Affiliation:
Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire AL9 7TA, United Kingdom. cbate@rvc.ac.uk
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MeSH Terms
Descriptor/Qualifier:
Acetylation
Animals
Cell Line
Cell Membrane / genetics,  metabolism*
Cholesterol / genetics,  metabolism
GPI-Linked Proteins / genetics,  metabolism*
Mice
Phospholipases A2, Cytosolic / genetics,  metabolism
PrPC Proteins / genetics,  metabolism*
PrPSc Proteins / genetics,  metabolism
Prion Diseases / genetics,  metabolism,  therapy
Signal Transduction*
Chemical
Reg. No./Substance:
0/GPI-Linked Proteins; 0/PrPC Proteins; 0/PrPSc Proteins; 57-88-5/Cholesterol; EC 3.1.1.4/Phospholipases A2, Cytosolic
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