NR AXFG
AU Filesi,I.; Cardinale,A.; Mattei,S.; Biocca,S.
TI Selective re-routing of prion protein to proteasomes and alteration of its vesicular secretion prevent PrPsc formation
QU Journal of Neurochemistry 2007 Jun; 101(6): 1516-26
PT journal article; research support, non-u.s. gov't
AB Conversion of the cellular prion protein (PrPc) into the abnormal scrapie isoform (PrPsc) is the hallmark of prion diseases, which are fatal and transmissible neurodegenerative disorders. ER-retained anti-prion recombinant single-chain Fv fragments have been proved to be an effective tool for inhibition of PrPc trafficking to the cell surface and antagonize PrPsc formation and infectivity. In the present study, we have generated the secreted version of 8H4 intrabody (Sec-8H4) in order to compel PrPc outside the cells. The stable expression of the Sec-8H4 intrabodies induces proteasome degradation of endogenous prion protein but does not influence its glycosylation profile and maturation. Moreover, we found a dramatic diverting of PrPc traffic from its vesicular secretion and, most importantly, a total inhibition of PrPsc accumulation in NGF-differentiated Sec-8H4 PC12 cells. These results confirm that perturbing the intracellular traffic of endogenous PrPc is an effective strategy to inhibit PrPsc accumulation and provide convincing evidences for application of intracellular antibodies in prion diseases.
MH Animals; Cell Compartmentation; Chloroquine/pharmacology; Immunoglobulin Variable Region/immunology; Mice; PC12 Cells; PrPc Proteins/immunology/*metabolism; PrPsc Proteins/*biosynthesis/immunology; Prion Diseases/prevention & control; Protease Inhibitors/pharmacology; Proteasome Endopeptidase Complex/*metabolism; Protein Transport/drug effects; Rats
AD Department of Neuroscience and Laboratory of Clinical Biochemistry, University of Tor Vergata, Rome, Italy.
SP englisch
PO England