Dominant-negative inhibition of prion replication in transgenic mice

• DOI: 10.1073/pnas.182425299
• Publication Date: 2002-10-01T16:58:07Z
• Authors: Véronique Perrier; Kiyotoshi Kaneko; Jiri Safar; Julie Vergara; Patrick Tremblay; Stephen J. DeArmond; Fred E. Cohen; Stanley B. Prusiner; Andrew C. Wallace
• Keywords: PRNP; Gliosis

Our discovery of dominant-negative inhibition prion formation in cultured cells provided an explanation for the resistance some sheep to scrapie and humans Creutzfeldt–Jakob disease. To determine whether occurs vivo , we produced transgenic (Tg) mice expressing protein (PrP) with either Q167R or Q218K mutation alone combination wild-type (wt) PrP. Tg(MoPrP,Q167R) Prnp 0/0 mutant PrP at levels equal non-Tg remained healthy >550 days, indicating that inoculation prions did not cause Immunoblots brain homogenates histologic analysis reveal abnormalities. +/+ both wt exhibit neurologic dysfunction, but their brains revealed low pathogenic isoform (PrP Sc ), sections showed numerous vacuoles severe astrocytic gliosis 300 days after inoculation. Both Tg(MoPrP,Q218K) high transgene product >300 Neither nor neuropathologic changes were found. studies demonstrate although occurs, expression same level as does prevent completely. However, had no deleterious effects on support propagation.