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.

Filesi, I., Cardinale, A., Mattei, S., & Biocca, S. (2007). Selective re-routing of prion protein to proteasomes and alteration of its vesicular secretion prevent PrPSc formation. JOURNAL OF NEUROCHEMISTRY, 101(6), 1516-1526 [10.1111/j.1471-4159.2006.04439.x].

Selective re-routing of prion protein to proteasomes and alteration of its vesicular secretion prevent PrPSc formation

BIOCCA, SILVIA
2007

Abstract

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.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/12
English
Con Impact Factor ISI
benzyloxycarbonylleucylleucylleucinal; lactacystin; monoclonal antibody; monoclonal antibody 7A12; monoclonal antibody 8H4; monoclonal antibody 9E10; nerve growth factor receptor; prion protein; proteasome; single chain fragment variable antibody; animal cell; article; cell differentiation; cell vacuole; concentration response; controlled study; glycosylation; intracellular space; nonhuman; prion disease; priority journal; protein degradation; protein expression; protein processing; protein secretion; protein stability; protein synthesis; rat; Animals; Cell Compartmentation; Chloroquine; Immunoglobulin Variable Region; Mice; PC12 Cells; Prion Diseases; Protease Inhibitors; Proteasome Endopeptidase Complex; Protein Transport; PrPC Proteins; PrPSc Proteins; Rats
Filesi, I., Cardinale, A., Mattei, S., & Biocca, S. (2007). Selective re-routing of prion protein to proteasomes and alteration of its vesicular secretion prevent PrPSc formation. JOURNAL OF NEUROCHEMISTRY, 101(6), 1516-1526 [10.1111/j.1471-4159.2006.04439.x].
Filesi, I; Cardinale, A; Mattei, S; Biocca, S
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/30412
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