KDEL-tagged anti-prion intrabodies impair PrP lysosomal degradation and inhibit scrapie infectivity

• Published in: Biochemical and biophysical research communications Vol. 338; no. 4; pp. 1791 - 1797
• Main Authors: Vetrugno, Vito, Cardinale, Alessio, Filesi, Ilaria, Mattei, Sonia, Sy, Man-Sun, Pocchiari, Maurizio, Biocca, Silvia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-12-2005
• Subjects: Animals; Antibodies - pharmacology; Intrabodies; Intracellular Fluid - immunology; Lysosomal degradation; Lysosomes - metabolism; Mice; Oligopeptides - metabolism; PC12 Cells; Prion; Prions - immunology; Protein Sorting Signals; PrPC Proteins - metabolism; PrPSc Proteins - pathogenicity; Rats; ScFv; Scrapie - transmission; Scrapie infectivity; Prion; Lysosomal degradation; Scrapie infectivity; Intrabodies; ScFv
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2005.10.146

Transmissible spongiform encephalopathy or prion diseases are fatal neurodegenerative disorders characterized by the conversion of the cellular prion protein (PrP
C) into the infectious scrapie isoform (PrP
Sc). We have recently demonstrated that anti-prion intrabodies targeted to the lumen of the endoplasmic reticulum provide a simple and effective means to inhibit the transport of PrP
C to the cell surface. Here, we report that they completely block the traffic of mature full-length PrP
C molecules, impair prion lysosomal degradation, and interfere with the early phase of scrapie formation. Since anti-prion intrabodies efficiently block PrP
Sc accumulation in vitro, we investigated whether they could also antagonize scrapie infectivity in vivo. We found that mice intracerebrally injected with KDEL-8H4-NGF-differentiated PC12 cells infected with scrapie neither develop scrapie clinical signs nor brain damage. Furthermore, no protease-resistant PrP
Sc is detectable in brains of inoculated animals. These results indicate that anti-prion intrabody strategy may be effective against prion infection.