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Expression of unglycosylated mutated prion protein facilitates PrP^Sc formation in neuroblastoma cells infected with different prion strains

Institute for Neurodegenerative Diseases¹ and Departments of Neurology² and Biochemistry and Biophysics³, Box 0518, University of California, San Francisco, CA 94143-0518, USA

Author for correspondence: Stanley Prusiner. Fax +1 415 476 8386.

Prion replication involves conversion of the normal, host-encoded prion protein PrP^C, which is a sialoglycoprotein bound to the plasma membrane by a glycophosphatidylinositol anchor, into a pathogenic isoform, PrP^Sc. In earlier studies, tunicamycin prevented glycosylation of PrP^C in scrapie-infected mouse neuroblastoma (ScN2a) cells but it was still expressed on the cell surface and converted into PrP^Sc; mutation of PrP^C at glycosylation consensus sites (T182A, T198A) produced low steady-state levels of PrP that were insufficient to propagate prions in transgenic mice. By mutating asparagines to glutamines at the consensus sites, we obtained expression of unglycosylated, epitope-tagged MHM2PrP(N180Q,N196Q), which was converted into PrP^Sc in ScN2a cells. Cultures of uninfected neuroblastoma (N2a) cells transiently expressing mutated PrP were exposed to brain homogenates prepared from mice infected with the RML, Me7 or 301V prion strains. In each case, mutated PrP was converted into PrP^Sc as judged by Western blotting. These findings raise the possibility that the N2a cell line can support replication of different strains of prions.

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