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Removal of the glycosylphosphatidylinositol anchor from PrPSc by cathepsin D does not reduce prion infectivity

Lewis, PA; Properzi, F; Prodromidou, K; Clarke, AR; Collinge, J; Jackson, GS; (2006) Removal of the glycosylphosphatidylinositol anchor from PrPSc by cathepsin D does not reduce prion infectivity. BIOCHEM J , 395 443 - 448. 10.1042/BJ20051677. Gold open access

Abstract

According to the protein-only hypothesis of prion propagation, prions are composed principally of PrPSc, an abnormal conformational isoform of the prion protein, which, like its normal cellular precursor (PrPC), has a GPI (glycosylphosphatidylinositol) anchor at the C-terminus. To date, elucidating the role of this anchor on the infectivity of prion preparations has not been possible because of the resistance of PrPSc to the activity of PI-PLC (phosphoinositide specific phospholipase C), an enzyme which removes the GPI moiety from PrPc. Removal of the GPI anchor from PrPSc requires denaturation before treatment with PI-PLC, a process that also abolishes infectivity. To circurrivent this problem, we have removed the GPI anchor from PrPSc in RML (Rocky Mountain Laboratory)-prion-infected murine brain homogenate using the aspartic endoprotease cathepsin D. This enzyme eliminates a short sequence at the C-terminal end of PrP to which the GPI anchor is attached. We found that this modification has no effect (i) on an in vitro amplification model of PrPSc, (ii) on the prion titre as determined by a highly sensitive N2a-cell based bioassay, or (iii) in a mouse bioassay. These results show that the GPI anchor has little or no role in either the propagation of PrPSc or on prion infectivity.

Type: Article
Title: Removal of the glycosylphosphatidylinositol anchor from PrPSc by cathepsin D does not reduce prion infectivity
Open access status: An open access publication
DOI: 10.1042/BJ20051677
Publisher version: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC14227...
Keywords: cathepsin D, Creutzfeldt-Jakob disease (CJD), glycosylphosphatidylinositol, anchor (GPI anchor), prion, prion infectivity, ALZHEIMERS-DISEASE, PATHOGENIC MUTATIONS, PROTEIN, SCRAPIE, RESISTANT, AMPLIFICATION, ASSOCIATION, EXPRESSION, PRECURSOR, ENZYME
URI: http://discovery.ucl.ac.uk/id/eprint/145894
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