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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Safar, Jiri Kaneko, Kiyotoshi Wallace, Andrew C. Vergara, Julie Tremblay, Patrick Prusiner, Stanley B. Perrier, Véronique Cohen, Fred E. Dearmond, Stephen J. |
| Description | Author Affiliation: Perrier V ( Institute for Neurodegenerative Diseases and Departments of Pathology, Biochemistry and Biophysics, Cellular and Molecular Pharmacology, Medicine, and Neurology, University of California, San Francisco, CA 94143-0518, USA.); |
| Abstract | Our discovery of dominant-negative inhibition of prion formation in cultured cells provided an explanation for the resistance of some sheep to scrapie and humans to Creutzfeldt-Jakob disease. To determine whether dominant-negative inhibition occurs in vivo, we produced transgenic (Tg) mice expressing prion protein (PrP) with either the Q167R or Q218K mutation alone or in combination with wild-type (wt) PrP. Tg(MoPrP,Q167R)Prnp(0/0) mice expressing mutant PrP at levels equal to non-Tg mice remained healthy for >550 days, indicating that inoculation with prions did not cause disease. Immunoblots of brain homogenates and histologic analysis did not reveal abnormalities. Tg(MoPrP,Q167R)Prnp(+/+) mice expressing both mutant and wt PrP did not exhibit neurologic dysfunction, but their brains revealed low levels of the PrP pathogenic isoform (PrP(Sc)), and sections showed numerous vacuoles and severe astrocytic gliosis at 300 days after inoculation. Both Tg(MoPrP,Q218K)Prnp(0/0) and Tg(MoPrP,Q218K)Prnp(+/+) mice expressing high levels of the transgene product remained healthy for >300 days after inoculation. Neither PrP(Sc) nor neuropathologic changes were found. Our studies demonstrate that although dominant-negative inhibition of wt PrP(Sc) formation occurs, expression of the dominant-negative PrP at the same level as wt PrP does not prevent prion formation completely. However, expression of dominant-negative PrP alone had no deleterious effects on the mice and did not support prion propagation. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 20 |
| Volume Number | 99 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2002-10-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Genes, Dominant PrPSc Proteins Genetics Metabolism Prions Animals Brain Pathology Calibration Immunoassay Immunoblotting Mice Mice, Transgenic Polymorphism, Genetic Protein Conformation Protein Isoforms Scrapie Transgenes Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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