NR AXEM
AU Karpuj,M.V.; Giles,K.; Gelibter-Niv,S.; Scott,M.R.D.; Lingappa,V.R.; Szoka,F.C.Jr.; Peretz,D.; Denetclaw,W.; Prusiner,S.B.
TI Phosphorothioate oligonucleotides reduce PrP levels and prion infectivity in cultured cells
QU Molecular Medicine 2007 Mar-Apr; 13(3-4): 190-8
PT journal article; research support, n.i.h., extramural; research support, non-u.s. gov't
AB Prions are composed solely of the disease-causing prion protein (PrPsc) that is formed from the cellular isoform PrPc by a posttranslational process. Here we report that short phosphorothioate DNA (PS-DNA) oligonucleotides diminished the levels of both PrPc and PrPsc in prion-infected neuroblastoma (ScN2a) cells. The effect of PS-DNA on PrP levels was independent of the nucleotide sequence. The effective concentration (EC50) of PS-DNA required to achieve half-maximal diminution of PrPsc was approximately 70 nM, whereas the EC50 of PS-DNA for PrPc was more than 50-fold greater. This finding indicated that diminished levels of PrPsc after exposure to PS-DNA are unlikely to be due to decreased PrPc levels. Bioassays in transgenic mice demonstrated a substantial diminution in the prion infectivity after ScN2a cells were exposed to PS-DNAs. Whether PS-DNA will be useful in the treatment of prion disease in people or livestock remains to be established.
MH Animals; Binding, Competitive; Cell Survival/drug effects; Dose-Response Relationship, Drug; Fluoresceins; Fluorescent Dyes; Mice; Mice, Transgenic; Neuroblastoma/pathology; Oligonucleotides/chemistry/*pharmacology; Phosphates/*chemistry; PrPc Proteins/genetics/*metabolism; PrPsc Proteins/*metabolism; Prions/antagonists & inhibitors/genetics/*pathogenicity; Time Factors; Tumor Cells, Cultured
AD Institute for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, CA 94143-0518, USA.
SP englisch
PO USA