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Mutant prion protein acquires resistance to protease in mouse neuroblastoma cells

Institut für Neuropathologie, Universität Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany¹
Institut für Neuropathologie, Ludwig-Maximilians-Universität München, Marchioninistr. 17, D-81377 München, Germany²

Authors for correspondence: Hans Kretzschmar and Otto Windl. Fax +49 89 70954903. e-mail Hans.Kretzschmar{at}inp.med.uni-muenchen.de, Otto.Windl@inp.med.uni-muenchen.de

Conversion of the cellular isoform of the prion protein (PrP^C) into the pathogenic isoform (PrP^Sc) is thought to be the causative event in prion diseases. Biochemically, PrP^Sc differs from PrP^C in its partial resistance to proteinase K (PK). The amino acid sequence AGAAAAGA, comprising residues 112–119 of the murine PrP^C, has been shown to be amyloidogenic and evolutionarily conserved. To assess the effect of mutations at and around this hydrophobic sequence on protease resistance, the sequence was replaced either by alanines or by glycines and, in a third mutant, a large part surrounding this region was removed. The PrP mutant carrying substitutions of glycines for alanines showed PK resistance and aberrant proteolytic processing. Tetracycline-induced expression of this mutant indicated that resistance to protease is acquired concurrent with the synthesis of the protein. These findings indicate that mutations in the central hydrophobic region lead to immediate alterations in PrP structure and processing.